Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease

Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease 矿物质代谢紊乱与钙化性主动脉瓣疾病的发生和严重性相关 1 first-author 1 2 1 1 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:rjshenweifeng@126.com †E-mail:rjshenweifeng@126.com rjshenweifeng@126.com Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Objective: 2 We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease (CAVD) in patients with normal or mildly impaired renal function. Methods: 2 We measured serum levels of calcium, phosphate, alkaline phosphatase (AKP), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OHD), and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis (AVSc) ( n =164) or stenosis (AVS) ( n =96) and in 164 age- and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Results: 2 Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels (all P < 0.001). Similarly, osteocalcin, procollagen I N-terminal peptide, and β-isomerized type I collagen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS (all P < 0.001). In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding variables, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were independently associated with the presence and severity of CAVD. Conclusions: 2 This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism. 目的 2 探讨在肾功能正常或轻度受损（肾小球滤过率≥60ml/(min•1.73m 2 )）人群中矿物质代谢紊乱与钙化性主动脉瓣疾病的发生和严重性是否相关。 创新点 2 以具有代表性和临床价值的肾功能正常或轻度受损人群为研究对象，首次尝试通过骨转换生物标志物检测探讨钙化性主动脉瓣疾病的可能机制。 方法 2 入选260例经超声心动图诊断钙化性主动脉瓣疾病患者（164例钙化性主动脉瓣硬化，96例钙化性主动脉瓣狭窄）和164例年龄及性别匹配对照组人群，检测矿物质代谢和骨转换生化标志物，应用多因素回归分析矿物质代谢与钙化性主动脉瓣疾病的发生和严重性的关系，并初步探讨可能机制。结果显示，从对照组到钙化性主动脉瓣硬化至狭窄患者，血钙、血磷、碱性磷酸酶和甲状旁腺素（iPTH）水平进行性升高，25羟-维生素D（25-OHD）水平进行性降低，各组间差异具有统计学显著性（ P < 0.001）；同样，骨转换生化标志物骨钙素（BGP）、I型前胶原N端前肽（PINP）和β-胶原特殊序列（β-CTx）水平进行性升高，各组间差异具有统计学显著性（ P < 0.001）。在钙化性主动脉瓣狭窄患者中，iPTH水平与跨瓣峰值流速和平均跨瓣压差显著正相关，25-OHD则显著负相关。经校正相关因素后，多因素回归分析显示，血钙、血磷、碱性磷酸酶和iPTH水平升高及25-OHD水平下降和钙化性主动脉瓣疾病的发生和严重性密切相关。 结论 2 矿物质代谢紊乱与钙化性主动脉瓣疾病的发生和严重性密切相关，异常骨转换可能是其发生机制。 Valve heart disease Aortic stenosis Mineral metabolism Calcium Phosphate 瓣膜性心脏病 主动脉瓣狭窄 矿物质代谢 血钙 血磷 Introduction 1 Calcific aortic valve disease (CAVD), ranging from mild thickening of the cusp (i.e. aortic valve sclerosis (AVSc)) to severe aortic valve stenosis (AVS) with functional impairment, is a common acquired valvular disorder in the elderly, associated with significant morbidity and mortality (Freeman and Otto, 2005 2005 ). The prevalence of AVSc without obstruction of the left ventricular outflow tract is approximately 30% in adults aged over 65 years and about 50% in those beyond 85 years, whereas significant AVS is present in 2%–7% of adults over 65 years of age (Iung et al., 2003 2003 ). CAVD was once described as a passive degenerative and unmodifiable process. Thus, surgical valve replacement and transcatheter aortic valve implantation are considered to be the only established therapy for patients with severe symptomatic AVS. Recently, growing evidence demonstrates that CAVD also develops through an inflammatory process similar to atherosclerosis that can be possibly targeted with medical treatment (Rajamannan, 2009 2009 ; Yetkin and Waltenberger, 2009 2009 ). Unfortunately, several randomized, placebo-control trials have failed to show that use of statins retards the progression of AVS (Parolari et al., 2011 2011 ; Teo et al., 2011 2011 ), suggesting that despite similar risk factors and downstream mediators, atherogenesis is not pivotal to the pathogenesis of CAVD. Therefore, a strong impulse is emerging to further investigate the novel pathophysiological pathways and their modulation in order to prevent/delay the onset or progression of valve degeneration (Rajamannan et al., 2011 2011 ). Disturbance of mineral metabolism has been proposed as a potential etiology for aortic valve calcification in end-stage renal disease, malignancy, sarcoidosis, or hyperparathyroidism (Strickberger et al., 1987 1987 ; Stefenelli et al., 1993 1993 ; Kume et al., 2006 2006 ; Iwata et al., 2013 2013 ). However, its role in the development of CAVD for patients with relatively preserved renal function remains largely unknown. In this pair-matched case-control study, we sought to test the hypothesis that abnormal calcium and phosphate metabolism is associated with the presence and severity of CAVD in patients with normal or mildly impaired renal function. In addition, serum levels of bone turnover biomarkers, including osteocalcin, procollagen I N-terminal peptide (PINP), and β-isomerized type I collagen C-telopeptide breakdown products (β-CTx), were measured to elucidate the possible mechanisms. Materials and methods 1 Patient population 2 A total of 2659 consecutive patients referred for coronary angiography and echocardiography because of ischemic symptom in the Department of Cardiology at Shanghai Ruijin Hospital (China) between June 2012 and June 2013 were screened. Overall, 303 patients were diagnosed as having CAVD by transthoracic two-dimensional echocardiography and Doppler flow imaging. For the purpose of this study, we excluded patients with bicuspid aortic valve ( n =3), moderate/severe aortic regurgitation ( n =10), rheumatic valve disease ( n =3), moderate/severe renal insufficiency defined as estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m 2 ( n =12), or known primary hyperparathyroidism ( n =1), and those who were receiving anti-osteoporotic treatments ( n =14). Among the remaining 260 eligible patients, AVSc was detected in 164 patients and AVS was observed in 96 patients with a peak trans-aortic valve flow velocity ≥2.0 m/s (mean (3.8±1.0) m/s) (Fig. 1 1 ). CAG: coronary angiography; AVSc: aortic valve sclerosis; AVS: aortic valve stenosis We also selected 164 gender- and age-matched patients without CAVD in a 1:1 ratio as a control group. The study was approved by Shanghai Jiao Tong University Ethics Committee and conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent. Doppler echocardiography 2 For each patient, M-mode and two-dimensional echocardiography and pulsed and continuous-wave Doppler imaging were performed by two experienced observers blinded to biochemical measurements. AVSc was defined as aortic cusp thickening with normal excursion and a peak trans-aortic valve flow velocity <2.0 m/s. AVS was defined as increased echogenicity, thickening, or calcification of the leaflets with a peak trans-aortic valve flow velocity ≥2.0 m/s. Laboratory assessment 2 Peripheral venous blood was collected in the morning of angiography after an overnight fasting. Serum levels of calcium, phosphate, alkaline phosphatase (AKP), total cholesterol, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose, creatinine, aminotransferases, and creatinine kinase were determined using standard methods. Serum levels of 25-hydroxyvitamin D (25-OHD), osteocalcin, PINP, and β-CTx were measured using automatic electrochemiluminescence immunoassay (Cobas E601 analyzer, Roche Diagnostics, Mannheim, Germany). Intact parathyroid hormone (iPTH) was measured using an automatic chemiluminescence immunoassay analyzer (Abbott Architect i2000SR analyzer, Abbott Laboratories, Chicago, USA). All assays were done in duplicate by investigators blinded to the clinical and echo-Doppler findings. Definitions 2 Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medications. Type 2 diabetes mellitus was diagnosed according to the American Diabetes Association criteria, including glycosylated hemoglobin (HbA1c) ≥6.5%, fasting plasma glucose concentration ≥7.0 mmol/L, 2-h postprandial glucose concentration ≥11.1 mmol/L, or a random plasma glucose ≥11.1 mmol/L in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis (ADA, 2010 2010 ). Hypercholesterolemia was defined by total cholesterol > 5.2 mmol/L or under medical treatment. Kidney function was determined by eGFR using the modified Modification of Diet in Renal Disease (MDRD) formula. The severity of coronary artery disease was expressed by the number of significantly diseased coronary arteries (luminal diameter stenosis ≥50% in a major epicardial coronary artery and its main branch) and SYNTAX score ( http://www.syntaxscore.com http://www.syntaxscore.com ) assessed by two independent experienced operators. Hyperparathyroidism was defined as serum iPTH > 65 pg/ml. Statistical analysis 2 Continuous variables are expressed as mean±standard deviation (SD) and were analyzed using one-way analysis of variance (ANOVA). Categorical variables are presented as number and percentages, and were compared with a chi-square test. To determine the relationship between mineral metabolism disturbances and the presence and severity of CAVD, we compared mineral metabolism parameters, including serum calcium, phosphate, AKP, 25-OHD, and iPTH, between patients with and without AVSc and between patients with AVSc and those with AVS. In 96 patients with AVS, the relationship between mineral metabolism parameters and hemodynamic severity of CAVD was established by the Spearman correlation test. The association of mineral metabolism parameters with the presence and severity of CAVD was determined by a multivariate logistic regression model after adjusting for risk factors of coronary artery disease, body mass index, renal function, and coronary angiographic findings. A P -value of < 0.05 was considered to be statistically significant. All analyses were performed using SPSS statistical software for Windows Versions 13.0 (SPSS Inc., Chicago, IL, USA). Results 1 Baseline characteristics 2 Patients with AVSc did not significantly differ from controls with respect to cardiovascular risk and severity of coronary artery disease except for elevated serum levels of total and LDL-cholesterol (Table 1 1 ). There were no significant differences between patients with AVSc and those with AVS in cardiovascular risk and severity of coronary artery disease (Table 1 1 ). Data are expressed as mean±SD or as number (percentage). CAVD: calcific aortic valve disease; AVSc: aortic valve sclerosis; AVS: aortic valve stenosis. P 1 : control group vs. patients with AVSc; P 2 : patients with AVSc vs. those with AVS Variable Controls ( n =164) Patients with AVSc ( n =164) Patients with AVS ( n =96) P 1 P 2 Age (year) 73.2±7.5 73.2±7.5 74.1±8.0 1.000 0.402 Men 107 (65.2%) 107 (65.2%) 59 (61.5%) 1.000 0.540 Diabetes mellitus 56 (34.1%) 50 (30.5%) 29 (30.2%) 0.479 0.962 Hypertension 128 (78.0%) 126 (76.8%) 72 (75.0%) 0.792 0.738 Smoking (current or past) 42 (25.6%) 40 (24.4%) 21 (21.9%) 0.799 0.644 Hypercholesterolemia 51 (31.1%) 53 (32.3%) 25 (26.0%) 0.812 0.287 Total cholesterol (mmol/L) 3.77±1.06 4.07±0.94 4.17±1.07 0.007 0.396 HDL-cholesterol (mmol/L) 1.18±0.33 1.18±0.30 1.19±0.27 0.933 0.761 LDL-cholesterol (mmol/L) 2.27±0.85 2.45±0.81 2.54±0.86 0.040 0.402 Triglycerides (mmol/L) 1.51±0.92 1.51±0.90 1.45±0.74 0.963 0.586 Body mass index (kg/m 2 ) 24.2±2.6 24.4±3.5 23.8±3.4 0.458 0.120 Glomerular filtration rate (ml/min per1.73 m 2 ) 78.1±13.8 78.2±14.3 75.3±15.8 0.940 0.131 Coronary artery disease 91 (55.5%) 96 (58.5%) 50 (52.1%) 0.577 0.312  1-vessel 52 (57.1%) 55 (57.3%) 28 (56.0%) 0.724 0.466  2-vessel 30 (33.0%) 34 (35.4%) 17 (34.0%) 0.577 0.554  3-vessel 9 (9.9%) 7 (7.3%) 5 (10.0%) 0.608 0.727 SYNTAX score 12.26±7.38 12.91±7.00 12.59±7.22 0.591 0.797 Biochemical investigation 2 Stepwise increases were observed in serum levels of calcium, phosphate, AKP, iPTH, and biomarkers of bone turnover (osteocalcin, PINP, β-CTx) from control group to patients with AVS, with reverse changes for 25-OHD levels (for all comparisons, P < 0.001) (Table 2 2 ). In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to peak trans-aortic flow velocity ( r =0.428, P < 0.001; r =−0.235, P =0.021, respectively) and mean pressure gradient ( r =0.457, P < 0.001; r =−0.233, P =0.022, respectively) (Fig. 2 2 ). Data are expressed as mean±SD. iPTH: intact parathyroid hormone; 25-OHD: 25-hydroxyvitamin D; AKP: alkaline phosphatase; PINP: procollagen I N-terminal peptide; β-CTx: β-isomerized type I collagen C-telopeptide breakdown products; CAVD: calcific aortic valve disease; AVSc: aortic valve sclerosis; AVS: aortic valve stenosis. P 1 : control group vs. patients with AVSc; P 2 : patients with AVSc vs. those with AVS Variable Controls ( n =164) Patients with AVSc ( n =164) Patients with AVS ( n =96) P 1 P 2 6 Mineral metabolism parameters  Serum calcium (mg/dl) 8.39±0.44 8.79±0.33 9.11±0.57 <0.001 <0.001  Serum phosphate (mg/dl) 3.06±0.54 3.75±0.57 4.38±1.05 <0.001 <0.001  iPTH (pg/ml) 37.88±13.11 55.97±17.96 76.12±33.72 <0.001 <0.001  25-OHD (nmol/L) 58.48±20.80 39.27±16.31 32.32±18.58 <0.001 <0.001  AKP (U/L) 52.58±15.69 70.48±24.63 82.40±26.51 <0.001 <0.001 6 Biomarkers of bone turnover  Serum osteocalcin (ng/ml) 11.80±4.33 18.45±8.19 21.76±9.53 <0.001 <0.001  Serum PINP (ng/ml) 30.94±13.67 45.24±17.01 59.33±32.98 <0.001 <0.001  Serum β-CTx (ng/ml) 0.32±0.16 0.50±0.19 0.67±0.35 <0.001 <0.001 Serum levels of iPTH correlated positively (a, b), but 25-OHD inversely (c, d), with peak trans-aortic valve flow velocity and mean pressure gradient. iPTH: intact parathyroid hormone; 25-OHD: 25-hydroxyvitamin D Multivariate analysis 2 After adjusting for risk factors of coronary artery disease, body mass index, renal function, and number of disease coronary arteries, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were independently associated with the presence and severity of CAVD (Table 3 3 ). OR: odds ratio; CI: confidence interval; CAVD: calcific aortic valve disease; LDL: low density lipoprotein; AKP: alkaline phosphatase; 25-OHD: 25-hydroxyvitamin D; iPTH: intact parathyroid hormone 2 Variable 2 Univariate 2 Multivariate OR (95% CI) P -value OR (95% CI) P -value Presence of CAVD  Total cholesterol 1.355 (1.083–1.695) 0.008 0.873 (0.318–2.396) 0.793  LDL-cholesterol 1.320 (1.011–1.724) 0.041 1.014 (0.297–3.459) 0.982  Serum calcium 14.845 (7.298–30.197) <0.001 10.018 (3.364–29.835) <0.001  Serum phosphate 9.840 (5.721–16.922) <0.001 3.945 (1.955–7.959) <0.001  AKP 1.058 (1.041–1.076) <0.001 1.037 (1.013–1.062) 0.003  25-OHD 0.943 (0.930–0.957) <0.001 0.950 (0.932–0.969) <0.001  iPTH 1.077 (1.058–1.097) <0.001 1.068 (1.041–1.097) <0.001 Severity of CAVD  Serum calcium 5.662 (2.829–11.331) <0.001 6.984 (2.736–17.825) <0.001  Serum phosphate 3.275 (2.097–5.116) <0.001 3.665 (1.985–6.765) <0.001  AKP 1.018 (1.008–1.029) 0.001 1.016 (1.003–1.029) 0.019  25-OHD 0.975 (0.959–0.991) 0.002 0.971 (0.951–0.992) 0.006  iPTH 1.032 (1.020–1.044) <0.001 1.037 (1.021–1.053) <0.001 Discussion 1 The present study demonstrates an association of abnormal metabolism of calcium and phosphate with the presence and severity of CAVD in patients with normal or mildly impaired renal function, suggesting that medical treatment targeting mineral metabolism disturbance may be a novel strategy to retard the development and progression of CAVD. Relation between mineral metabolism disturbance and CAVD 2 Calcification has been shown to be an integral part of disease onset and progression in the histopathologic studies of AVS (Parolari et al., 2009 2009 ; Yetkin and Waltenberger, 2009 2009 ). Previous studies have shown that dysregulation of calcium and phosphate metabolism with high parathyroid hormone and low 25-hydroxyvitamin levels correlated with the severity of AVS in patients with preserved renal function with or without coronary artery disease (Mills et al., 2004 2004 ; Linhartová et al., 2008 2008 ; Akat et al., 2010 2010 ). However, the majority of these patients had severe AVS. Recently, Akat et al. ( 2009 2009 ) reported that foci of micro-calcification have been observed in the early stage of CAVD (AVSc or mild AVS). In the Cardiovascular Health Study, elevated phosphate levels, but not calcium, parathyroid hormone, or 25-OHD levels in serum, were associated with AVSc in a community-based cohort of older adults (Linefsky et al., 2011 2011 ). The lack of association between major mineral metabolism measurements except serum phosphate and AVSc may be, at least partly, related to the exclusion of those with known cardiovascular disease. In comparison with previous reports (Mills et al., 2004 2004 ; Linhartová et al., 2008 2008 ; Akat et al., 2010 2010 ), our study population was specially selected, as all patients had AVSc or AVS by trans-thoracic two-dimensional echocardiography and Doppler flow imaging and were in normal or mildly impaired renal function. Our results suggest that mineral metabolism disturbances were independently associated with both presence and severity of CAVD in these patients, irrespective of presence or absence of cardiovascular disease. The potential mechanism responsible for the association between abnormal calcium and phosphate metabolism and valve calcification is likely to be complex. Soft tissue calcification has been thought to be an entirely passive physicochemical process that is driven by serum levels of calcium and phosphate (O'Neill, 2007 2007 ). Recent evidence increasingly suggests that this process involves cellular events, extracellular matrix composition, and other regulators of mineral metabolism, supporting a notion that CAVD is also an active course (Rajamannan, 2009 2009 ; Yetkin and Waltenberger, 2009 2009 ). Parathyroid hormone and 25-OHD are the most important regulators of calcium and phosphate metabolism, particularly for both bone formation and osteoblast activity. In this study, there were significant differences in bone turnover markers between patients with AVSc or AVS and those without, suggesting that CAVD may be a state with decreased bone turnover, similar to the features of osteoporosis in elderly people. In the COFRASA study, Hekimian et al. ( 2013 2013 ) reported that progression of AVS was associated with calcium-phosphorus metabolism and a bone resorptive remodeling. Recently, Nagy et al. ( 2013 2013 ) found a close relation between circulating mediators of bone homeostasis and severity of AVS. Clinical implications 2 Since the burden of CAVD is expected to increase rapidly with aging of the population, strategies to slow down or reverse the progression of CAVD become important (Iung et al., 2003 2003 ). Our study showed that abnormal lipid metabolism reflected by elevated serum levels of total and LDL-cholesterol was not an independent factor for the presence of CAVD. In contrast, degeneration of heart valve tissue may be caused by mineral metabolism disturbances. The effect of osteoporosis therapy has been investigated because of an association between aortic valve calcification and low skeletal bone mineral density (Aksoy et al., 2005 2005 ). Several small observational studies demonstrated a possible link between use of bisphosphonates and slowing of AVS progression (Skolnick et al., 2009 2009 ; Sterbakova et al., 2010 2010 ; Innasimuthu and Katz, 2011 2011 ), although such beneficial effects may be not remarkable in older women (Aksoy et al., 2012 2012 ). Taken together, prospective randomized clinical studies are certainly needed to evaluate the role of regulation of calcium and phosphate metabolism for preventing progression of CAVD especially at its early stage. Study limitations 2 We recognized limitations in our study. The study presented here is cross-sectional, thereby allowing us to detect association, but not to infer causality or formulate predictions. Furthermore, several exclusion criteria may introduce selection biases, and the relationship between mineral metabolism disturbance and progression of CAVD was not assessed. Finally, valvular fibrosis, as well as calcification, restricts cusp movement, and CAVD may be more appropriately viewed as a fibrocalcific disease. Conclusions 1 This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Large-scale prospective studies are needed to assess the effects of medical treatment targeting mineral metabolism disturbance on the development and progression of CAVD. References ADA (American Diabetes Association) Standards of medical care in diabetes 2010 . 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Molecular and cellular mechanisms of aortic stenosis Compliance with ethics guidelines Zhen-kun YANG, Chen YING, Hong-yan ZHAO, Yue-hua FANG, Ying CHEN, and Wei-feng SHEN declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article. 10.1631/jzus.B1400292 Project supported by the Science and Technology Commission of Shanghai Municipality (No. 114119a8800), China 2014-10-29 2015-04-09 2015-03-12 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2015 2015 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 05 16