Endocrine Care 581
Osteoprotegerin is Secreted Into the Coronary Circulation: A Possible Association with the ReninAngiotensin System and Cardiac Hypertrophy
Affiliations
Key words ▶ angiotensin II ● ▶ concentric hypertrophy ● ▶ remodeling ●
received 28.11.2013 accepted 03.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375611 Published online: May 8, 2014 Horm Metab Res 2014; 46: 581–586 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence T. Tsuruda, MD, PhD Department of Internal Medicine Circulatory and Body Fluid Regulation Faculty of Medicine University of Miyazaki 5200 Kihara Kiyotake Miyazaki 889-1692 Japan Tel.: + 81/985/85 0872 Fax: + 81/985/85 6596 [email protected]
S. Koyama1, T. Tsuruda1, T. Ideguchi1, J. Kawagoe1, H. Onitsuka1, T. Ishikawa1, H. Date1, K. Hatakeyama2, Y. Asada2, J. Kato3, K. Kitamura1 1
Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 3 Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan 2
Abstract
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The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67 ± 10 years old, male 57 %, hypertension 73 %, coronary artery disease 50 %) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7 ± 4.1 vs. 6.7 ± 3.6 pmol/l, p < 0.001). The trans-cardiac OPG concentration was significantly (p = 0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients sub-
Introduction
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Epidemiological studies have shown that age is the dominant risk factor for cardiovascular diseases [1]. Arterial and cardiac structure, function, and its composition change with age, but these are accelerated in the presence of diabetes mellitus, dyslipidemia, or hypertension. Left ventricular hypertrophy (LVH) is primarily an adaptive response against the increased vascular resistance, and the concentric increase in cardiac mass often occurs in hypertensive patients [2]. Sustained elevations in vascular resistance with aging further promotes LVH, in turn increasing the risk for cardiovascular events [3]. The reninangiotensin system (RAS) plays an important role in raising systemic blood pressure by regulating sodium reabsorption and increasing peripheral vascular resistance, but it also stimulates hypertrophy of cardiomyocytes and interstitial
group who did not take an ACEI/ARB (n = 27), the trans-cardiac OPG level was positively correlated with age (r = 0.396, p = 0.041) and relative wall thickness of left ventricle (r = 0.534, p = 0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p = 0.004). Moreover, trans-cardiac OPG was significantly (p = 0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased ( ≥ 116 for males, or ≥ 104 for females, g/m2) or not (p = 0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system. Supporting Information for this article is available online at http://www.thieme-connect.de/ ejournals/toc/hmr
hyperplasia [4]. The levels of angiotensin II (Ang II), angiotensin converting enzyme (ACE), and its receptor increase with age in the heart and vasculature [5–7] and appear to regulate age-related cardiovascular remodeling [1]. Most of these actions mediate the Ang II type 1 receptor, and blockade of the RAS with either an angiotensin converting enzyme inhibitor (ACEI) or an Ang II type 1 receptor blocker (ARB) delays the cardiovascular structural change and damage, extending the life span in rodents [8, 9]. Osteoprotegerin (OPG) is a secretory glycoprotein belonging to the tumor necrosis factor (TNF) receptor super-family [10, 11]. OPG inhibits osteoclastogenesis by competitively inhibiting the binding of the receptor activator of the nuclear factor-κb ligand (RANKL) [12] to its receptor RANK. OPG mRNA is widely distributed in various organs associated with bone metabolism, such as thyroid, kidney, and the intestines, but it
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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Authors
582 Endocrine Care
Patients and Methods
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We notified the patients in writing and on the homepage regarding the study, and each participant gave written informed consent. This study was approved by the Human Investigation Review Committee of the University of Miyazaki (No. 787) and conformed to the principles outlined in the Declaration of Helsinki [25].
Echocardiography Echocardiography was performed using an ATL Philips IE33 Ultrasound machine (Garnerville, NY, USA) as previously described [28]. In brief, two-dimensional imaging was performed in a standard fashion using the parasternal long- or short-axis and apical 2- or 4-chamber views. The LV end-diastolic or systolic dimensions were obtained using the 2D-mode view on electrocardiogram. After a careful analysis of regional contractile abnormalities, the LV ejection fraction was determined by either biplane apical views using a modified Simpson’s method or the formula: (LVDd)2 – (LVDs)2 divided by (LVDd)2 (LVDd: LV end-diastolic dimension; LVDs: LV end-systolic dimension) when the wall motion was normal. LV mass index (LVMI) was estimated according to its dimension and wall thickness using the method of Devereux and associates [29], and it was divided by the body surface area. LVH was defined as an LVMI > 116 g/m2 in men and > 104 g/m2 in women [30]. The mean wall thickness was calculated as: IVSTd + LVPWTd divided by 2 (IVSTd: intraventricular septal thickness in diastole; LVPWTd: left ventricular posterior wall thickness in diastole). The relative wall thickness was calculated as: IVSTd + LVPWTd divided by LVDd. The reference cut point value for increased relative wall thickness was 0.45 or greater [2, 31].
Patients This study included 56 patients (67 ± 10 years old, male 57 %) admitted to the First Department of Internal Medicine, University of Miyazaki Hospital. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or taking any antihypertensive medicine, whereas ACEI/ARB was also prescribed when systolic LV dysfunction is present in the absence of hypertension; diabetes mellitus as fasting plasma glucose level ≥ 126 mg/dl, 2-h postprandial glucose ≥ 200 mg/dl, or taking any medicine for diabetes mellitus; and dyslipidemia as a fasting plasma total cholesterol level ≥ 220 mg/dl and/or triglyceride ≥ 150 mg/dl or taking any medicine for dyslipidemia. Estimated glomerular filtration rate (eGFR) was calculated using the equation for the Modification of Diet in Renal Disease [26].
Statistical analysis Data analyses were performed using IBM SPSS statistics 21 (SPSS Japan, Tokyo, Japan). We used Student’s t-test for 2 continuous variables and Fisher’s exact test for nominal values such as numbers and percentages. The difference in individual OPG levels between CA and CS was analyzed using a paired t-test. The unadjusted and adjusted associations of trans-cardiac OPG levels with other clinical parameters were evaluated by Pearson’s rank-correlation coefficient and linear regression. Quantitative variables were coded as 0 = men, 1 = women, or any type of comorbidity and medicines (0 = no and 1 = yes) in the analyses. Values are shown as absolute numbers, percentage or the mean ± standard deviation. Statistical significance was accepted when p is < 0.05.
Cardiac catheterization We performed cardiac catheterization and assessed hemodynamics such as pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure (LVEDP). We then collected blood samples simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography [27]. The position of the catheter tip in the coronary sinus was confirmed by injecting contrast dye medium. Blood samples were mixed with 10.5 mg of 2-({2-[bis(carboxymethyl)amino] ethyl}(carboxymethyl)amino)acetic acid disodium salt and centrifuged at 3 000 rpm at 4 °C for 15 min; the samples were then stored at − 30 °C or colder until use.
OPG and RANKL measurements The plasma OPG and RANKL concentrations were measured in duplicate by Immundiagnostik’s ELISA according to the manufacturer’s instructions (Cat. No. Bl-20402, Bl-20422 H, BIOMEDICA, Vienna, Austria). Absorption was determined at 450 nm, using 620 nm as a reference. The results of the samples were calculated using a 4PL-algorithm, with 0.14 pmol/l and 0.08 pmol/l as the detection limit, respectively. The intra-assay and interassay coefficients of variation were each less than 10 %. Transcardiac OPG secretion was determined as the difference in OPG levels between CS and CA [delta OPG (CS-CA)].
Results
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Patients’ characteristics ▶ Table 1 summarizes the characteristics of 56 patients enrolled ● in this study. Seventy-three percent of the subjects were hypertensive and were treated with anti-hypertensive medicines (54 %, calcium channel antagonist; 20 %, beta-blocker; 52 %, ACEI/ ARB). Half of the patients had no apparent coronary artery stenosis, and 82 % of them had an LV ejection fraction greater than 50 %.
OPG is secreted into the coronary circulation ▶ Fig. 1 shows that the concentration of OPG obtained from the ● coronary sinus (CS) was significantly higher than that from the orifice of the left coronary artery (CA) (7.7 ± 4.1 vs. 6.7 ± 3.6 pmol/l, p < 0.0001). We further analyzed whether the trans-cardiac OPG level [delta (CS-CA)] was correlated with any clinical variables, and found that it was negatively associated with ACEI/ARB intake at the catheterization study (r = − 0.312, p = 0.019). However, we did not find any association with other types of comorbidity, medicines, or any parameters such as age, sex, body mass index, LV diastolic and systolic dimensions, LVMI, LV ejection fraction,
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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is also found in the heart and vasculature [13, 14]. Proinflammatory cytokines such as TNF-α, transforming growth factor-β1, and Ang II induce OPG synthesis in vitro [15–17]. The serum OPG level appears to be associated with age, increasing in concentration in postmenopausal women [18] and in general population in the elderly [19]. Circulating OPG levels also reflect the severity of cardiovascular disorders such as coronary artery disease, cardiac hypertrophy, and heart failure [14, 20–24]. However, the source(s) of circulating OPG have not yet been determined. Based upon these reports, we conducted experiments to explore whether OPG is released into the coronary circulation and whether it is associated with left ventricular structure and function.
Endocrine Care 583
Table 1 Patients’ characteristics. 56 67 ± 10 (32–86) 57 24 ± 4 (17–36) 65 ± 27 (25–160) 73 34 38
28 7 11 10 Fig. 1 OPG concentration obtained from the orifice of the left coronary artery (CA) and the coronary sinus (CS) (n = 56). *p < 0.001 vs. CA.
1 1 3 1 3
patients who were already taking an ACEI/ARB had a high prevalence of hypertension and diabetes mellitus, whereas ACEI/ARB was also prescribed to 10.3 % (3/29) patients who have impaired LV function without hypertension. Moreover, these patients were prescribed aspirin more frequently and exhibited an increased systolic LV dimension with reduced contractility. ▶ Fig. 2 shows that the OPG level was higher at CS than CA in ● the group of patients without ACEI/ARB (7.8 ± 4.3 vs. 6.3 ± 3.1 pmol/l, p < 0.001); however, this trend was diminished in patients in the group with ACEI/ARB intake (7.6 ± 4.1 vs. 7.1 ± 4.1 pmol/l, p = 0.126).
54 20 52 23 38 1.2 ± 0.3 (0.6–2.2) 1.2 ± 0.4 (0.8–3.3) 4.4 ± 0.7 (1.5–6.8) 2.9 ± 0.8 (1.5–5.2) 1.2 ± 0.2 (0.9–1.9) 65 ± 15 (20–87) 155 ± 51 (54–330) 0.54 ± 0.13 (0.35–0.88)
Trans-cardiac OPG level vs. left ventricular geometry
12 ± 5 (5–32) 14 ± 6 (0–30)
Data are expressed as the mean ± standard deviation, absolute number (n) or percentages Values in parentheses indicate the range of the absolute values eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy;
In the group of patients without ACEI/ARB, the trans-cardiac OPG level positively correlated with age, LVPWTd, mean wall ▶ Table 3). In multivariate thickness, and relative wall thickness (● linear regression analysis, relative wall thickness predicts the trans-cardiac OPG level (regression co-efficient 0.664, 95 % con▶ Fig. 3a fidence interval: 3.153–14.634, p = 0.004, Table S2). ● shows that the trans-cardiac OPG was significantly (p = 0.021) increased in subjects with relative wall thickness greater than 0.45 but that it did not differ whether the LVMI increased or not ▶ Fig. 3b). (p = 0.627, ●
DCM: Dilated cardiomyopathy; ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVEF: Left ventricular ejection fraction; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure
mean wall thickness, relative wall thickness, PCWP or LVEDP (data not shown). In multivariate linear regression analysis, ACEI/ARB intake remained to be the independent value for determining the OPG step-up (regression coefficient − 0.410, 95 % confidence interval: − 2.797 to − 0.020, p = 0.047, Table S1) after adjustment for aspirin intake, proportion of hypertension and/or diabetes mellitus, LV ejection fraction, LVMI, and relative wall thickness. We also measured RANKL level at the both sites, but the concentrations were too low to be detected in all samples.
OPG level at orifice of left coronary artery and coronary sinus with or without RAS inhibition We reassessed the OPG levels and categorized the results into 2 ▶ Table 2, groups: with or without RAS inhibition. As shown in ●
Discussion
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The OPG level obtained from the peripheral blood has been reported to reflect the severity of cardiovascular diseases [32, 33], but the source of OPG remains to be determined. Simultaneous CA and CS sampling allows the regional quantitative analyses for any indices released into the coronary circulation, with the minimal dilution effect as seen in the peripheral blood [34]. The present study offers the evidence for the intra-cardiac production of OPG, and our results advance the hypothesis that OPG is related to the development of cardiac hypertrophy [21, 24]. This study did not show the exact cellular source for OPG in the coronary circulation, but we speculate that various cell types constituting the vasculature [17, 35, 36] and heart [14, 22, 37] are possible contributors to OPG secretion. Blockade of Ang II type 1 receptor has been shown to decrease the OPG production in human aneurysmal tissues [36]. We speculate that both cardiomyocytes and fibroblasts are candidates for sources of OPG, and the Ang II type 1 receptor-mediated down-
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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n Age Male ( %) Body mass index (kg/m2) eGFR (ml/min/1.73 m2) Hypertension ( %) Dyslipidemia ( %) Diabetes mellitus ( %) Coronary artery disease No. of stenosis 0 (n) 1 (n) 2 (n) 3 (n) Valvular disease Aortic stenosis (n) Mitral regurgitation (n) Cardiomyopathy HCM (n) DCM (n) Undefined (n) Medication Calcium channel antagonist ( %) Beta-blocker ( %) ACEI/ARB ( %) Statin ( %) Aspirin ( %) Echocardiogram IVSTd (cm) LVPWTd (cm) LVDd (cm) LVDs (cm) MWT (cm) LVEF ( %) LVMI (g/m2) RWT Hemodynamics PCWP mean (mm Hg) LVEDP (mm Hg)
584 Endocrine Care
Table 2 Patients’ characteristics without (–) or with ( + ) RAS inhibition. ACEI/ARB Number of patients Age Sex (male, %) Body mass index (kg/m2) eGFR (ml/min/1.73 m2) Hypertension ( %) Dyslipidemia ( %) Diabetes mellitus ( %) Coronary artery disease ( %) Valvular disease ( %) Cardiomyopathy HCM ( %) DCM ( %) Undefined ( %) Medication Calcium channel blocker ( %) Beta-blocker ( %) Statin ( %) Aspirin ( %) Echocardiogram LVEF ( %) IVSTd (cm) LVPWTd (cm) LVDd (cm) LVDs (cm) MWT (cm) LVMI (g/m2) RWT Hemodynamics PCWP, mean (mm Hg) LVEDP (mm Hg) OPG (pmol/l) CA CS
p-Value
(–)
(+)
27 66 ± 10 52 23 ± 4 68 ± 26 52 30 22 37 7
29 69 ± 10 62 24 ± 4 63 ± 28 90 38 52 62 0
0.319 0.590 0.409 0.428 0.001 0.580 0.029 0.108 0.228
7 0 4
3 3 7
0.605 1.000 1.000
56 19 19 19
52 21 28 55
0.795 1.000 0.532 0.006
73 ± 9 1.1 ± 0.3 1.1 ± 0.2 4.3 ± 0.5 2.6 ± 0.5 1.1 ± 0.3 149 ± 55 0.52 ± 0.13
60 ± 15 1.2 ± 0.2 1.2 ± 0.2 4.6 ± 0.8 3.2 ± 1.0 1.2 ± 0.2 161 ± 47 0.55 ± 0.14
11 ± 4 13 ± 6
13 ± 6 15 ± 6
0.145 0.467
6.3 ± 3.1 7.8 ± 4.3
7.1 ± 4.1 7.6 ± 4.1
0.377 0.864
< 0.001 0.112 0.256 0.237 0.005 0.138 0.393 0.412
Data are expressed as the mean ± standard deviation, absolute number (n) or percentages ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; LVEF: Left ventricular ejection fraction; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure; CA: Orifice of the left coronary artery; CS: Coronary sinus
duce the report showing that OPG concentration was decreased in the coronary circulation in patients with aortic stenosis [37]. The discrepancy between the 2 studies remains unclear, but the result may depend on the patient population enrolled: our study and others included patients who exhibited LV ejection fraction Table 3 Correlation of trans-cardiac OPG level with clinical variables without (–) or with ( + ) RAS inhibition. ACEI/ARB (–) n = 27 r Age Sex Body mass index eGFR Hypertension Dyslipidemia Diabetes mellitus Coronary artery disease Valvular disease Cardiomyopathy HCM DCM Undefined Medication Calcium channel blocker Beta-blocker Statin Aspirin Echocardiogram LVEF IVSTd LVPWTd LVDd LVDs MWT LVMI RWT Hemodynamics PCWP (mean) LVEDP
( + ) n = 29 p
r
p
0.396 − 0.355 − 0.074 − 0.159 0.173 − 0.154 − 0.029 0.037 − 0.248
0.041 0.069 0.713 0.429 0.389 0.442 0.887 0.853 0.212
0.047 0.069 − 0.104 0.237 0.053 − 0.104 − 0.034 − 0.323 n.d.
0.808 0.721 0.592 0.217 0.783 0.591 0.861 0.088
− 0.240 n.d. 0.307
0.228 0.119
− 0.143 − 0.043 − 0.098
0.459 0.823 0.612
0.059
0.771
0.054
0.780
− 0.113 0.143 0.103
0.573 0.476 0.609
− 0.297 − 0.092 0.125
0.118 0.636 0.517
− 0.050 0.273 0.562 − 0.205 − 0.192 0.457 0.036 0.534
0.810 0.168 0.002 0.305 0.338 0.016 0.857 0.004
0.168 − 0.095 − 0.181 0.151 − 0.046 − 0.112 0.103 − 0.265
0.385 0.623 0.347 0.434 0.814 0.563 0.595 0.164
− 0.009 − 0.174
0.963 0.396
− 0.015 − 0.213
0.945 0.341
ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; LVEF: Left ventricular ejection fraction; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure n.d.: Not determined, due to the absence of case
Fig. 2 OPG concentration obtained from the orifice of the left coronary artery (CA) and the coronary sinus (CS) divided into 2 groups without ACEI/ARB (a, n = 27) and with ACEI/ARB (b, n = 29). *p < 0.001 vs. CA.
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
signaling would be involved in the mechanism of production during the cardiac hypertrophy. But, this hypothesis should be proven by in vitro experiment. The present study did not repro-
Endocrine Care 585
*
10
17
Fig. 3 Trans-cardiac OPG level in relation to relative wall thickness (RWT) a and left ventricular mass index (LVMI) b in patients without an ACEI/ ARB intake. Data are shown as the mean ± standard deviation. Number in the bar graph indicates number of patients.
b
7
greater than 50 % (82 % vs. 40 %), coronary artery disease (50 % vs. 32 %), or aortic stenosis (2 % vs. 100 %). It is noted that the OPG step-up in the coronary circulation was dependent on the RAS inhibition in this study. Therefore, we reanalyzed all of the patients by categorizing them into 2 groups (with or without an ACEI/ARB prescription), and found that the increase in OPG stepup in the coronary circulation was decreased in those taking an ACEI/ARB. This result could be partly interpreted as a trend for the increase in OPG at the orifice of the left coronary artery in patients taking an ACEI/ARB, who have high prevalence of hypertension, diabetes mellitus, and impaired LV systolic contractility, all of which may potentially increase the circulating OPG level [21, 22, 33, 38]. The clinical setting makes complex to interpret, but the magnitude of OPG step-up was clearly different between the groups. More importantly, ACEI/ARB intake was the independent variable after adjustment for these comorbidities. Taken together, we speculate that a relationship exists between OPG secretion and RAS activation in the heart. Ang II stimulates cardiomyocyte hypertrophy and fibroblast growth directly [4], and we showed that the trans-cardiac OPG level positively correlated with LV wall thickness in the patient subgroup without ACEI/ARB. This observation was compatible with the prior 2 cohort studies [21, 24] and further indicates that the cardiac secretion of OPG is likely to reflect the left ventricular geometry, called “concentric remodeling/concentric hypertrophy” [2, 31]. Overall, this study advances our understanding of OPG associated with the development of cardiac hypertrophy, possibly in interaction with RAS. The pathophysiological roles of OPG in the heart remain to be elucidated. OPG exerts favorable effects by counteracting the RANKL-mediated actions, such as the induction of apoptosis, chemotaxis, and the activation of matrix metalloproteinases [10, 11, 39]. Moreover, recent studies have shown that OPG may have RANKL-independent actions in vascular endothelial cells [40, 41] and smooth muscle cells [42, 43]. We speculate that Ang II type 1 receptor-mediated OPG secretion may represent a defense mechanism against RAS that promotes ventricular remodeling. Further studies are warranted to clarify the pathological roles of the OPG-RAS relationship in ventricular remodeling using animal models, such as those genetically lacking the OPG gene. In summary, this study suggests that OPG is secreted into coronary circulation and is associated with the development of concentric remodeling/hypertrophy in interaction with RAS.
Study Limitation
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This is a small observational study with a heterogeneous patient population. This study was conducted based on the experiments
20
showing that Ang II induced OPG synthesis both in vitro and in ex vivo culture [16, 36], but we are not sure that our observation is merely an epi-phenomenon. In addition, we neither measured renin activity, circulating Ang I or Ang II due to their instability in the stored plasma [44] nor referred to the dose or duration of ACEI/ARB intake until the cardiac catheterization. It would strengthen our observations if we could see the temporal change in trans-cardiac OPG levels before and after RAS inhibition in individual patients.
Acknowledgements
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This study was supported by grants-in-aid for Scientific Research (C) (20590830 to T. T.), Exploratory Research (19659090 to Y. A.) from the Ministry of Education, Culture, Sport, Science, and Technology, Japan; and grants-in-aids from the Japan Cardiovascular Research Foundation (to T. T.), Mitsubishi Pharma Research Foundation, and Takeda Science Foundation (to T. T.).
Conflict of Interest
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The authors declare that they have no conflicts of interest in the authorship or publication of this contribution.
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Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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a
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Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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586 Endocrine Care
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Osteoprotegerin is Secreted Into the Coronary Circulation: A Possible Association with the ReninAngiotensin System and Cardiac Hypertrophy
Affiliations
Key words ▶ angiotensin II ● ▶ concentric hypertrophy ● ▶ remodeling ●
received 28.11.2013 accepted 03.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375611 Published online: May 8, 2014 Horm Metab Res 2014; 46: 581–586 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence T. Tsuruda, MD, PhD Department of Internal Medicine Circulatory and Body Fluid Regulation Faculty of Medicine University of Miyazaki 5200 Kihara Kiyotake Miyazaki 889-1692 Japan Tel.: + 81/985/85 0872 Fax: + 81/985/85 6596 [email protected]
S. Koyama1, T. Tsuruda1, T. Ideguchi1, J. Kawagoe1, H. Onitsuka1, T. Ishikawa1, H. Date1, K. Hatakeyama2, Y. Asada2, J. Kato3, K. Kitamura1 1
Department of Internal Medicine, Circulatory and Body Fluid Regulation, University of Miyazaki, Miyazaki, Japan Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 3 Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan 2
Abstract
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The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67 ± 10 years old, male 57 %, hypertension 73 %, coronary artery disease 50 %) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7 ± 4.1 vs. 6.7 ± 3.6 pmol/l, p < 0.001). The trans-cardiac OPG concentration was significantly (p = 0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients sub-
Introduction
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Epidemiological studies have shown that age is the dominant risk factor for cardiovascular diseases [1]. Arterial and cardiac structure, function, and its composition change with age, but these are accelerated in the presence of diabetes mellitus, dyslipidemia, or hypertension. Left ventricular hypertrophy (LVH) is primarily an adaptive response against the increased vascular resistance, and the concentric increase in cardiac mass often occurs in hypertensive patients [2]. Sustained elevations in vascular resistance with aging further promotes LVH, in turn increasing the risk for cardiovascular events [3]. The reninangiotensin system (RAS) plays an important role in raising systemic blood pressure by regulating sodium reabsorption and increasing peripheral vascular resistance, but it also stimulates hypertrophy of cardiomyocytes and interstitial
group who did not take an ACEI/ARB (n = 27), the trans-cardiac OPG level was positively correlated with age (r = 0.396, p = 0.041) and relative wall thickness of left ventricle (r = 0.534, p = 0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p = 0.004). Moreover, trans-cardiac OPG was significantly (p = 0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased ( ≥ 116 for males, or ≥ 104 for females, g/m2) or not (p = 0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system. Supporting Information for this article is available online at http://www.thieme-connect.de/ ejournals/toc/hmr
hyperplasia [4]. The levels of angiotensin II (Ang II), angiotensin converting enzyme (ACE), and its receptor increase with age in the heart and vasculature [5–7] and appear to regulate age-related cardiovascular remodeling [1]. Most of these actions mediate the Ang II type 1 receptor, and blockade of the RAS with either an angiotensin converting enzyme inhibitor (ACEI) or an Ang II type 1 receptor blocker (ARB) delays the cardiovascular structural change and damage, extending the life span in rodents [8, 9]. Osteoprotegerin (OPG) is a secretory glycoprotein belonging to the tumor necrosis factor (TNF) receptor super-family [10, 11]. OPG inhibits osteoclastogenesis by competitively inhibiting the binding of the receptor activator of the nuclear factor-κb ligand (RANKL) [12] to its receptor RANK. OPG mRNA is widely distributed in various organs associated with bone metabolism, such as thyroid, kidney, and the intestines, but it
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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Authors
582 Endocrine Care
Patients and Methods
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We notified the patients in writing and on the homepage regarding the study, and each participant gave written informed consent. This study was approved by the Human Investigation Review Committee of the University of Miyazaki (No. 787) and conformed to the principles outlined in the Declaration of Helsinki [25].
Echocardiography Echocardiography was performed using an ATL Philips IE33 Ultrasound machine (Garnerville, NY, USA) as previously described [28]. In brief, two-dimensional imaging was performed in a standard fashion using the parasternal long- or short-axis and apical 2- or 4-chamber views. The LV end-diastolic or systolic dimensions were obtained using the 2D-mode view on electrocardiogram. After a careful analysis of regional contractile abnormalities, the LV ejection fraction was determined by either biplane apical views using a modified Simpson’s method or the formula: (LVDd)2 – (LVDs)2 divided by (LVDd)2 (LVDd: LV end-diastolic dimension; LVDs: LV end-systolic dimension) when the wall motion was normal. LV mass index (LVMI) was estimated according to its dimension and wall thickness using the method of Devereux and associates [29], and it was divided by the body surface area. LVH was defined as an LVMI > 116 g/m2 in men and > 104 g/m2 in women [30]. The mean wall thickness was calculated as: IVSTd + LVPWTd divided by 2 (IVSTd: intraventricular septal thickness in diastole; LVPWTd: left ventricular posterior wall thickness in diastole). The relative wall thickness was calculated as: IVSTd + LVPWTd divided by LVDd. The reference cut point value for increased relative wall thickness was 0.45 or greater [2, 31].
Patients This study included 56 patients (67 ± 10 years old, male 57 %) admitted to the First Department of Internal Medicine, University of Miyazaki Hospital. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or taking any antihypertensive medicine, whereas ACEI/ARB was also prescribed when systolic LV dysfunction is present in the absence of hypertension; diabetes mellitus as fasting plasma glucose level ≥ 126 mg/dl, 2-h postprandial glucose ≥ 200 mg/dl, or taking any medicine for diabetes mellitus; and dyslipidemia as a fasting plasma total cholesterol level ≥ 220 mg/dl and/or triglyceride ≥ 150 mg/dl or taking any medicine for dyslipidemia. Estimated glomerular filtration rate (eGFR) was calculated using the equation for the Modification of Diet in Renal Disease [26].
Statistical analysis Data analyses were performed using IBM SPSS statistics 21 (SPSS Japan, Tokyo, Japan). We used Student’s t-test for 2 continuous variables and Fisher’s exact test for nominal values such as numbers and percentages. The difference in individual OPG levels between CA and CS was analyzed using a paired t-test. The unadjusted and adjusted associations of trans-cardiac OPG levels with other clinical parameters were evaluated by Pearson’s rank-correlation coefficient and linear regression. Quantitative variables were coded as 0 = men, 1 = women, or any type of comorbidity and medicines (0 = no and 1 = yes) in the analyses. Values are shown as absolute numbers, percentage or the mean ± standard deviation. Statistical significance was accepted when p is < 0.05.
Cardiac catheterization We performed cardiac catheterization and assessed hemodynamics such as pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure (LVEDP). We then collected blood samples simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography [27]. The position of the catheter tip in the coronary sinus was confirmed by injecting contrast dye medium. Blood samples were mixed with 10.5 mg of 2-({2-[bis(carboxymethyl)amino] ethyl}(carboxymethyl)amino)acetic acid disodium salt and centrifuged at 3 000 rpm at 4 °C for 15 min; the samples were then stored at − 30 °C or colder until use.
OPG and RANKL measurements The plasma OPG and RANKL concentrations were measured in duplicate by Immundiagnostik’s ELISA according to the manufacturer’s instructions (Cat. No. Bl-20402, Bl-20422 H, BIOMEDICA, Vienna, Austria). Absorption was determined at 450 nm, using 620 nm as a reference. The results of the samples were calculated using a 4PL-algorithm, with 0.14 pmol/l and 0.08 pmol/l as the detection limit, respectively. The intra-assay and interassay coefficients of variation were each less than 10 %. Transcardiac OPG secretion was determined as the difference in OPG levels between CS and CA [delta OPG (CS-CA)].
Results
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Patients’ characteristics ▶ Table 1 summarizes the characteristics of 56 patients enrolled ● in this study. Seventy-three percent of the subjects were hypertensive and were treated with anti-hypertensive medicines (54 %, calcium channel antagonist; 20 %, beta-blocker; 52 %, ACEI/ ARB). Half of the patients had no apparent coronary artery stenosis, and 82 % of them had an LV ejection fraction greater than 50 %.
OPG is secreted into the coronary circulation ▶ Fig. 1 shows that the concentration of OPG obtained from the ● coronary sinus (CS) was significantly higher than that from the orifice of the left coronary artery (CA) (7.7 ± 4.1 vs. 6.7 ± 3.6 pmol/l, p < 0.0001). We further analyzed whether the trans-cardiac OPG level [delta (CS-CA)] was correlated with any clinical variables, and found that it was negatively associated with ACEI/ARB intake at the catheterization study (r = − 0.312, p = 0.019). However, we did not find any association with other types of comorbidity, medicines, or any parameters such as age, sex, body mass index, LV diastolic and systolic dimensions, LVMI, LV ejection fraction,
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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is also found in the heart and vasculature [13, 14]. Proinflammatory cytokines such as TNF-α, transforming growth factor-β1, and Ang II induce OPG synthesis in vitro [15–17]. The serum OPG level appears to be associated with age, increasing in concentration in postmenopausal women [18] and in general population in the elderly [19]. Circulating OPG levels also reflect the severity of cardiovascular disorders such as coronary artery disease, cardiac hypertrophy, and heart failure [14, 20–24]. However, the source(s) of circulating OPG have not yet been determined. Based upon these reports, we conducted experiments to explore whether OPG is released into the coronary circulation and whether it is associated with left ventricular structure and function.
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Table 1 Patients’ characteristics. 56 67 ± 10 (32–86) 57 24 ± 4 (17–36) 65 ± 27 (25–160) 73 34 38
28 7 11 10 Fig. 1 OPG concentration obtained from the orifice of the left coronary artery (CA) and the coronary sinus (CS) (n = 56). *p < 0.001 vs. CA.
1 1 3 1 3
patients who were already taking an ACEI/ARB had a high prevalence of hypertension and diabetes mellitus, whereas ACEI/ARB was also prescribed to 10.3 % (3/29) patients who have impaired LV function without hypertension. Moreover, these patients were prescribed aspirin more frequently and exhibited an increased systolic LV dimension with reduced contractility. ▶ Fig. 2 shows that the OPG level was higher at CS than CA in ● the group of patients without ACEI/ARB (7.8 ± 4.3 vs. 6.3 ± 3.1 pmol/l, p < 0.001); however, this trend was diminished in patients in the group with ACEI/ARB intake (7.6 ± 4.1 vs. 7.1 ± 4.1 pmol/l, p = 0.126).
54 20 52 23 38 1.2 ± 0.3 (0.6–2.2) 1.2 ± 0.4 (0.8–3.3) 4.4 ± 0.7 (1.5–6.8) 2.9 ± 0.8 (1.5–5.2) 1.2 ± 0.2 (0.9–1.9) 65 ± 15 (20–87) 155 ± 51 (54–330) 0.54 ± 0.13 (0.35–0.88)
Trans-cardiac OPG level vs. left ventricular geometry
12 ± 5 (5–32) 14 ± 6 (0–30)
Data are expressed as the mean ± standard deviation, absolute number (n) or percentages Values in parentheses indicate the range of the absolute values eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy;
In the group of patients without ACEI/ARB, the trans-cardiac OPG level positively correlated with age, LVPWTd, mean wall ▶ Table 3). In multivariate thickness, and relative wall thickness (● linear regression analysis, relative wall thickness predicts the trans-cardiac OPG level (regression co-efficient 0.664, 95 % con▶ Fig. 3a fidence interval: 3.153–14.634, p = 0.004, Table S2). ● shows that the trans-cardiac OPG was significantly (p = 0.021) increased in subjects with relative wall thickness greater than 0.45 but that it did not differ whether the LVMI increased or not ▶ Fig. 3b). (p = 0.627, ●
DCM: Dilated cardiomyopathy; ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVEF: Left ventricular ejection fraction; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure
mean wall thickness, relative wall thickness, PCWP or LVEDP (data not shown). In multivariate linear regression analysis, ACEI/ARB intake remained to be the independent value for determining the OPG step-up (regression coefficient − 0.410, 95 % confidence interval: − 2.797 to − 0.020, p = 0.047, Table S1) after adjustment for aspirin intake, proportion of hypertension and/or diabetes mellitus, LV ejection fraction, LVMI, and relative wall thickness. We also measured RANKL level at the both sites, but the concentrations were too low to be detected in all samples.
OPG level at orifice of left coronary artery and coronary sinus with or without RAS inhibition We reassessed the OPG levels and categorized the results into 2 ▶ Table 2, groups: with or without RAS inhibition. As shown in ●
Discussion
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The OPG level obtained from the peripheral blood has been reported to reflect the severity of cardiovascular diseases [32, 33], but the source of OPG remains to be determined. Simultaneous CA and CS sampling allows the regional quantitative analyses for any indices released into the coronary circulation, with the minimal dilution effect as seen in the peripheral blood [34]. The present study offers the evidence for the intra-cardiac production of OPG, and our results advance the hypothesis that OPG is related to the development of cardiac hypertrophy [21, 24]. This study did not show the exact cellular source for OPG in the coronary circulation, but we speculate that various cell types constituting the vasculature [17, 35, 36] and heart [14, 22, 37] are possible contributors to OPG secretion. Blockade of Ang II type 1 receptor has been shown to decrease the OPG production in human aneurysmal tissues [36]. We speculate that both cardiomyocytes and fibroblasts are candidates for sources of OPG, and the Ang II type 1 receptor-mediated down-
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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n Age Male ( %) Body mass index (kg/m2) eGFR (ml/min/1.73 m2) Hypertension ( %) Dyslipidemia ( %) Diabetes mellitus ( %) Coronary artery disease No. of stenosis 0 (n) 1 (n) 2 (n) 3 (n) Valvular disease Aortic stenosis (n) Mitral regurgitation (n) Cardiomyopathy HCM (n) DCM (n) Undefined (n) Medication Calcium channel antagonist ( %) Beta-blocker ( %) ACEI/ARB ( %) Statin ( %) Aspirin ( %) Echocardiogram IVSTd (cm) LVPWTd (cm) LVDd (cm) LVDs (cm) MWT (cm) LVEF ( %) LVMI (g/m2) RWT Hemodynamics PCWP mean (mm Hg) LVEDP (mm Hg)
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Table 2 Patients’ characteristics without (–) or with ( + ) RAS inhibition. ACEI/ARB Number of patients Age Sex (male, %) Body mass index (kg/m2) eGFR (ml/min/1.73 m2) Hypertension ( %) Dyslipidemia ( %) Diabetes mellitus ( %) Coronary artery disease ( %) Valvular disease ( %) Cardiomyopathy HCM ( %) DCM ( %) Undefined ( %) Medication Calcium channel blocker ( %) Beta-blocker ( %) Statin ( %) Aspirin ( %) Echocardiogram LVEF ( %) IVSTd (cm) LVPWTd (cm) LVDd (cm) LVDs (cm) MWT (cm) LVMI (g/m2) RWT Hemodynamics PCWP, mean (mm Hg) LVEDP (mm Hg) OPG (pmol/l) CA CS
p-Value
(–)
(+)
27 66 ± 10 52 23 ± 4 68 ± 26 52 30 22 37 7
29 69 ± 10 62 24 ± 4 63 ± 28 90 38 52 62 0
0.319 0.590 0.409 0.428 0.001 0.580 0.029 0.108 0.228
7 0 4
3 3 7
0.605 1.000 1.000
56 19 19 19
52 21 28 55
0.795 1.000 0.532 0.006
73 ± 9 1.1 ± 0.3 1.1 ± 0.2 4.3 ± 0.5 2.6 ± 0.5 1.1 ± 0.3 149 ± 55 0.52 ± 0.13
60 ± 15 1.2 ± 0.2 1.2 ± 0.2 4.6 ± 0.8 3.2 ± 1.0 1.2 ± 0.2 161 ± 47 0.55 ± 0.14
11 ± 4 13 ± 6
13 ± 6 15 ± 6
0.145 0.467
6.3 ± 3.1 7.8 ± 4.3
7.1 ± 4.1 7.6 ± 4.1
0.377 0.864
< 0.001 0.112 0.256 0.237 0.005 0.138 0.393 0.412
Data are expressed as the mean ± standard deviation, absolute number (n) or percentages ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; LVEF: Left ventricular ejection fraction; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure; CA: Orifice of the left coronary artery; CS: Coronary sinus
duce the report showing that OPG concentration was decreased in the coronary circulation in patients with aortic stenosis [37]. The discrepancy between the 2 studies remains unclear, but the result may depend on the patient population enrolled: our study and others included patients who exhibited LV ejection fraction Table 3 Correlation of trans-cardiac OPG level with clinical variables without (–) or with ( + ) RAS inhibition. ACEI/ARB (–) n = 27 r Age Sex Body mass index eGFR Hypertension Dyslipidemia Diabetes mellitus Coronary artery disease Valvular disease Cardiomyopathy HCM DCM Undefined Medication Calcium channel blocker Beta-blocker Statin Aspirin Echocardiogram LVEF IVSTd LVPWTd LVDd LVDs MWT LVMI RWT Hemodynamics PCWP (mean) LVEDP
( + ) n = 29 p
r
p
0.396 − 0.355 − 0.074 − 0.159 0.173 − 0.154 − 0.029 0.037 − 0.248
0.041 0.069 0.713 0.429 0.389 0.442 0.887 0.853 0.212
0.047 0.069 − 0.104 0.237 0.053 − 0.104 − 0.034 − 0.323 n.d.
0.808 0.721 0.592 0.217 0.783 0.591 0.861 0.088
− 0.240 n.d. 0.307
0.228 0.119
− 0.143 − 0.043 − 0.098
0.459 0.823 0.612
0.059
0.771
0.054
0.780
− 0.113 0.143 0.103
0.573 0.476 0.609
− 0.297 − 0.092 0.125
0.118 0.636 0.517
− 0.050 0.273 0.562 − 0.205 − 0.192 0.457 0.036 0.534
0.810 0.168 0.002 0.305 0.338 0.016 0.857 0.004
0.168 − 0.095 − 0.181 0.151 − 0.046 − 0.112 0.103 − 0.265
0.385 0.623 0.347 0.434 0.814 0.563 0.595 0.164
− 0.009 − 0.174
0.963 0.396
− 0.015 − 0.213
0.945 0.341
ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin II type 1 receptor blocker; eGFR: Estimated glomerular filtration rate; HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; LVEF: Left ventricular ejection fraction; IVSTd: Intraventricular septal thickness in diastole; LVPWTd: Left ventricular posterior wall thickness in diastole; LVDd: Left ventricular dimension in diastole; LVDs: Left ventricular dimension in systole; MWT: Mean wall thickness; LVMI: Left ventricular mass index; RWT: Relative wall thickness; PCWP: Pulmonary capillary wedge pressure; LVEDP: Left ventricular end-diastolic pressure n.d.: Not determined, due to the absence of case
Fig. 2 OPG concentration obtained from the orifice of the left coronary artery (CA) and the coronary sinus (CS) divided into 2 groups without ACEI/ARB (a, n = 27) and with ACEI/ARB (b, n = 29). *p < 0.001 vs. CA.
Koyama S et al. Osteoprotegerin and Cardiac Hypertrophy … Horm Metab Res 2014; 46: 581–586
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signaling would be involved in the mechanism of production during the cardiac hypertrophy. But, this hypothesis should be proven by in vitro experiment. The present study did not repro-
Endocrine Care 585
*
10
17
Fig. 3 Trans-cardiac OPG level in relation to relative wall thickness (RWT) a and left ventricular mass index (LVMI) b in patients without an ACEI/ ARB intake. Data are shown as the mean ± standard deviation. Number in the bar graph indicates number of patients.
b
7
greater than 50 % (82 % vs. 40 %), coronary artery disease (50 % vs. 32 %), or aortic stenosis (2 % vs. 100 %). It is noted that the OPG step-up in the coronary circulation was dependent on the RAS inhibition in this study. Therefore, we reanalyzed all of the patients by categorizing them into 2 groups (with or without an ACEI/ARB prescription), and found that the increase in OPG stepup in the coronary circulation was decreased in those taking an ACEI/ARB. This result could be partly interpreted as a trend for the increase in OPG at the orifice of the left coronary artery in patients taking an ACEI/ARB, who have high prevalence of hypertension, diabetes mellitus, and impaired LV systolic contractility, all of which may potentially increase the circulating OPG level [21, 22, 33, 38]. The clinical setting makes complex to interpret, but the magnitude of OPG step-up was clearly different between the groups. More importantly, ACEI/ARB intake was the independent variable after adjustment for these comorbidities. Taken together, we speculate that a relationship exists between OPG secretion and RAS activation in the heart. Ang II stimulates cardiomyocyte hypertrophy and fibroblast growth directly [4], and we showed that the trans-cardiac OPG level positively correlated with LV wall thickness in the patient subgroup without ACEI/ARB. This observation was compatible with the prior 2 cohort studies [21, 24] and further indicates that the cardiac secretion of OPG is likely to reflect the left ventricular geometry, called “concentric remodeling/concentric hypertrophy” [2, 31]. Overall, this study advances our understanding of OPG associated with the development of cardiac hypertrophy, possibly in interaction with RAS. The pathophysiological roles of OPG in the heart remain to be elucidated. OPG exerts favorable effects by counteracting the RANKL-mediated actions, such as the induction of apoptosis, chemotaxis, and the activation of matrix metalloproteinases [10, 11, 39]. Moreover, recent studies have shown that OPG may have RANKL-independent actions in vascular endothelial cells [40, 41] and smooth muscle cells [42, 43]. We speculate that Ang II type 1 receptor-mediated OPG secretion may represent a defense mechanism against RAS that promotes ventricular remodeling. Further studies are warranted to clarify the pathological roles of the OPG-RAS relationship in ventricular remodeling using animal models, such as those genetically lacking the OPG gene. In summary, this study suggests that OPG is secreted into coronary circulation and is associated with the development of concentric remodeling/hypertrophy in interaction with RAS.
Study Limitation
▼
This is a small observational study with a heterogeneous patient population. This study was conducted based on the experiments
20
showing that Ang II induced OPG synthesis both in vitro and in ex vivo culture [16, 36], but we are not sure that our observation is merely an epi-phenomenon. In addition, we neither measured renin activity, circulating Ang I or Ang II due to their instability in the stored plasma [44] nor referred to the dose or duration of ACEI/ARB intake until the cardiac catheterization. It would strengthen our observations if we could see the temporal change in trans-cardiac OPG levels before and after RAS inhibition in individual patients.
Acknowledgements
▼
This study was supported by grants-in-aid for Scientific Research (C) (20590830 to T. T.), Exploratory Research (19659090 to Y. A.) from the Ministry of Education, Culture, Sport, Science, and Technology, Japan; and grants-in-aids from the Japan Cardiovascular Research Foundation (to T. T.), Mitsubishi Pharma Research Foundation, and Takeda Science Foundation (to T. T.).
Conflict of Interest
▼
The authors declare that they have no conflicts of interest in the authorship or publication of this contribution.
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