Background: Achilles tendons are the most common sites of tendon xanthomas that are commonly caused by disturbance of lipid metabolism. Achilles tendon thickening is the early characteristic of Achilles tendon xanthomas. The relationship between Achilles tendon thickness (ATT) and LDL-C levels, and risk factors of ATT in patients with hypercholesterolemia, have thus far been poorly documented. Methods: A total of 205 individuals, aged 18-75 years, were enrolled from March 2014 to March 2015. According to the LDL-C levels and the “Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults”, all subjects were divided into 3 groups: normal group (LDL-C < 3.37 mmol/L, n = 51); borderline LDL-C group (3.37 mmol/L ≤ LDL-C ≤ 4.12 mmol/L, n = 50); and hypercholesterolemia group (LDL ≥ 4.14 mmol/L, n = 104). ATT was measured using a standardized digital radiography method and the results were compared among the 3 groups. The correlation between ATT and serum LDL-C levels was analyzed by Pearson’s correlation, and the risk factors of ATT were determined by the logistic regression model. Results: ATT in borderline LDL-C group was 8.24 ± 1.73 mm, markedly higher than 6.05 ± 0.28 mm of normal group (P < 0.05). ATT in hypercholesterolemia group was 9.42 ± 3.63 mm which was significantly higher than that of normal group (P < 0.005) and that of borderline LDL-C group (P < 0.05). There was a positive correlation between the serum LDL-C levels and ATT (r = 0.346, P < 0.001). The serum LDL-C level was a risk factor (OR = 1.871, 95% CI: 1.067-3.280) while the levels of HDL-C (OR = 0.099, 95% CI: 0.017-0.573) and Apo AI (OR = 0.035, 95% CI: 0.003-0.412) were protective factors of ATT. Conclusions: ATT might serve as a valuable auxiliary diagnostic index for hypercholesterolemia and used for the assessment and management of cardiovascular disease. Keywords: Low density lipoprotein cholesterol, Hypercholesterolemia, Achilles tendon xanthoma, Achilles tendon thickness, Cardiovascular disease, Digital radiography Background and thickest tendon in the body, is the most common site Tendinous xanthomas, consisting mainly of lipids and of tendonous xanthomas . An early sign of Achilles ten- monocyte-derived foam cells, are commonly caused by don xanthomas is Achilles tendon thickening, which can be lipoprotein metabolism disorders such as familial hyper- quantitatively measured by standardized digital radiography cholesterolemia (FH) . Tendon xanthomas are independ- (DR) [7, 8]. It has been shown that Achilles tendon thick- ently associated with the presence and burden of coronary ness (ATT) is a risk factor of cardiovascular disease (CVD) atherosclerosis [2–5]. The Achilles tendon, the strongest in patients with FH . However, the relationship between ATT and the degree of hypercholesterolemia particularly that of low density lipoprotein cholesterol (LDL-C), and * Correspondence: firstname.lastname@example.org factors associated with ATT in patients with hypercholes- Department of Cardiology, the Third People′s Hospital of Hainan Province, 1154 Jiefang Road, Sanya 572000, Hainan, China terolemia have thus far been poorly documented. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Lipids in Health and Disease (2018) 17:131 Page 2 of 7 In this study, we used a standardized digital radiog- was approved by the Institutional Review Committee of The raphy method to measure ATT in patients with hyper- Third People′s Hospital of Hainan Province. cholesterolemia and in subjects with normal and borderline LDL-C, and compared the results. The rela- Clinical examination tionship between ATT and LDL-C levels, and positive The age, gender, height, weight, body mass index (BMI), and negative predictors for ATT are described. fasting glucose levels and blood pressure of all subjects were recorded. Two milliliters of venous blood was collected after overnight fasting and centrifuged within Methods an hour for the measurement of serum LDL-C which Study subjects was completed using a standard method at the Depart- A total of 205 individuals, aged 18-75 years, were enrolled ment of Laboratory Medicine of The Third People′s between March 2014 and March 2015. Based on LDL-C Hospital of Hainan Province. levels, subjects were assigned to one of three tertiles de- ATT was measured by standardized digital radiography scribed by the Joint Committee for Developing Chinese with the following imaging parameters: 50 kV, 5 mAs, guidelines on Prevention and Treatment of Dyslipidemia in 0.05 mSv/image, and the distance from the X-ray Adults : normal LDL-C (LDL-C < 3.37 mmol/L, n = 51); source to the Achilles tendon was 120 cm . Sub- borderline LDL-C (3.37 mmol/L ≤ LDL-C ≤ 4.12 mmol/L, jects were positioned with the leg and the foot form- n = 50); and high LDL-C (LDL ≥ 4.14 mmol/L, n = 104). A ing a 90 degree angle. The thickest part of Achilles pilot study of 8 participants in each tertile was first per- tendon, between the heel and 8 cm above the heel, formed to determine sample size, which showed that the was measured (Fig. 1). ATT mean value in normal group, borderline LDL-C group and high LDL-C group was 5.88 mm, 7.50 mm and 8.89, Statistical methods respectively, with the highest standard deviation of 1.25 Statistical analyses were carried out using the SPSS statistical seen in the high LDL-C group. Using these preliminary package (19.0). Continuous variables were presented as data, the sample size required to detect a significant differ- mean values ± standard deviation (SD), and categorical ence in ATT was calculated with an online program variables are expressed as percentages and analyzed by the (http://powerandsamplesize.com/Calculators/Compare-k- Chi-square test. A one-way analysis of variance followed by Means/1-Way-ANOVA-Pairwise), and the results showed the Least Significant Difference (LSD) t test was performed that 15 subjects in each group are needed, ensuring that to compare continuous variables. Pearson’s correlation was the power of the test is 80% with type I error of 0.05. All used to analyze the correlation between the level of LDL-C patients with hypercholesterolemia (high LDL-C group) and ATT. Univariate and multivariable logistic regression were newly diagnosed, and had not received any lipid- models were used to analyze the risk factors of ATT. lowering therapy prior to participating in this study. None P < 0.05 was considered statistically significant. of the subjects in the normal or borderline LDL-C groups were taking lipid-lowering therapy. Patients with conditions Results that could affect Achilles tendon thickness such as tendinitis, Study subjects tenosynovitis, bursitis, tuberculum arthriticum, rheumatoid The demographic information and clinical characteris- arthritis, Achilles tendon injury or prior Achilles tendon tics of all 3 groups are shown in Table 1. There were no surgery were excluded from enrollment. All enrolled significant differences in gender ratio, age, height, subjects provided written informed consent, and the study weight, BMI and blood pressure (systolic and diastolic Fig. 1 Measurement of ATT by digital radiography. Panel (a) shows the measuring platform and ruler. For ATT measurement, the subject was side-lying with the leg and the foot forming a 90 degree angle (panel b) and the thickest part of Achilles tendon between the heel and 8 cm above the heel was measured (panel c) Wang et al. Lipids in Health and Disease (2018) 17:131 Page 3 of 7 Table 1 Demographics and clinical characteristics of all groups Normal Borderline LDL-C hypercholesterolemia Number (M/F) n = 51 (26/25) n = 50 (28/22) n = 104 (54/50) Age (years) 56.90 ± 7.46 51.52 ± 9.57 53.13 ± 10.86 Height (cm) 161.80 ± 6.02 160.61 ± 6.54 161.78 ± 7.27 Weight (kg) 56.55 ± 5.34 59.00 ± 11.28 60.55 ± 10.21 BMI (kg/m ) 21.56 ± 1.01 22.75 ± 3.34 23.07 ± 3.00 SBP (mmHg) 139.50 ± 19.78 128.16 ± 12.95 132.65 ± 14.78 DBP (mmHg) 86.00 ± 11.59 80.89 ± 10.34 85.33 ± 10.03 Δ# ATT (mm) 6.05 ± 0.28 8.24 ± 1.73* 9.42 ± 3.63 Comorbidities Hypertension n =4 n =15 n =22 Diabetes n =0 n =8 n =9 Continuous data were expressed as mean ± standard deviation M male, F female, BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, and ATT Achilles tendon thickness * P < 0.05 compared with normal group; Δ P < 0.05 compared with borderline LDL-C group; and # P < 0.005 compared with normal group blood pressure) among the three groups. Four individ- measurement in individuals from each group are shown uals had systolic hypertension (systolic blood pressure in Figs. 2, 3, and 4. average > 140 mmHg on repeated measurements) in the normal LDL-C group, 15 in the borderline LDL-C group Correlation between ATT and LDL-C levels and 22 in high LDL-C group. There were 0, 8, and 9 Analysis of correlation between ATT and LDL-C levels cases of diabetes in normal LDL-C, borderline LDL-C, showed a correlation coefficient of 0.346 (P < 0.001), and and high LDL-C groups respectively. Patients in the high there was a positive correlation as shown in Fig. 5. LDL-C group had the highest ATT, followed by those in the borderline LDL-C group. ATT was lowest in the Results of univariate logistic regression analysis normal LDL-C group. Statistical analysis showed that As shown in Table 2, univariate logistic regression analysis ATT in the borderline LDL-C group was markedly using ATT as the dependent variable, and gender, age, higher than that of the normal group, and ATT in the height, weight, BMI, systolic blood pressure, diastolic high LDL-C group was significantly higher than in the blood pressure, the fasting glucose level, levels of total other 2 groups (Table 1). Representative images of ATT cholesterol (TC), high density lipoprotein cholesterol Fig. 2 Representative images of ATT measurement in a subject with normal LDL-C. A male who was 66-year-old had an ATT of 7.5 mm (his serum LDL-C was 2.97 mmol/L) Wang et al. Lipids in Health and Disease (2018) 17:131 Page 4 of 7 Fig. 3 Representative images of ATT measurement in a subject with borderline LDL-C. A female who was 58-year-old had an ATT of 7.0 mm (her serum LDL-C was 3.85 mmol/L) (HDL-C), LDL-C, ApoA1, ApoB and lipoprotein(a) levels of HDL-C and ApoA1 were protective factors of (Lp(a)) as independent variables revealed that height, ATT (Table 3). BMI, TC, HDL-C, LDL-C and ApoA1 were associated with ATT (P <0.05). Discussion Hypercholesterolemia, diagnosed based on blood lipoprotein profiles with TC ≥ 6.22 mmol/L or LDL-C ≥ 4.14 mmol/L Results of multivariable regression analysis , can result in deposition and accumulation of Multivariable regression analysis was performed using cholesterol-rich materials on tendons forming tendon indexes which were demonstrated to be related to ATT xanthomas. As the Achilles tendon is a common site of lipid in univariate analysis. The results showed that only the deposition, its thickness can provide an early indicator of level of LDL-C remained a risk factor for ATT, while xanthoma formation . Although ultrasonography has Fig. 4 Representative images of ATT measurement in a patient with hypercholesterolemia. A male who was 67-year-old had an ATT of 13.5 mm (his serum LDL-C was 5.46 mmol/L) Wang et al. Lipids in Health and Disease (2018) 17:131 Page 5 of 7 Fig. 5 Analysis of correlation between ATT and LDL-C levels. The correlation coefficient was 0.346 between Achilles tendon thickness and serum LDL-C levels (P < 0.001) been used for the measurement of ATT [11–15], the standardized digital radiography method to measure ATT methodology has not been standardized . As there is no and found that; 1) ATT was significantly higher in patients neighboring tissue to serve as a reliable reference, the with hypercholesterolemia than in the other 2 groups, 2) subjective nature of ultrasonography for the evaluation of ATT was positively correlated with serum LDL-C levels diffuse changes in tendon echogenicity is an additional and, 3) the serum LDL-C level was an independent risk limitation . Therefore, in this study we adopted a factor, while the HDL-C and ApoA1 levels were protective factors of ATT. The presence of tendon xanthomas has been recog- Table 2 The results of univariate logistic regression analysis nized as a diagnostic marker for FH [5, 11–17]. How- Variable β S.E Wald P value OR 95% CI ever, few studies have explored the association between Gender −0.602 0.408 2.183 0.120 0.548 0.246-1.217 ATT and LDL-C levels. Ebeling et al. reported that pa- Ages 0.010 0.020 0.229 0.632 1.010 0.971-1.050 tients with heterozygous familial hypercholesterolemia Height 0.062 0.030 4.160 0.041 1.064 1.002-1.129 had higher ATT compared with healthy controls, and Weight 0.006 0.011 0.371 0.542 1.007 0.986-1.028 ATT was positively related to total cholesterol levels BMI 0.196 0.068 8.271 0.004 1.271 1.064-1.390 . Junyent et al. observed that, compared with other dyslipidemic or normolipidemic controls, patients with TC 0.277 0.134 4.243 0.039 1.139 1.014-1.715 FH had higher ATT which was positively correlated with LDL-C 0.869 0.239 13.274 0.000 2.385 1.494-3.807 LDL-C levels . These data align well with our findings, HDL-C −3.573 0.720 24.628 0.000 0.028 0.007-0.115 Apo AI −5.084 1.027 24.484 0.000 0.006 0.001-0.046 Table 3 The results of multivariable logistic regression analysis Apo B −0.209 0.533 0.153 0.695 0.812 0.285-2.238 Variable β S.E Wald P value OR 95% CI Lp (a) 0.001 0.001 0.983 0.321 1.001 0.999-1.003 Height 0.071 0.047 2.269 0.132 1.073 0.979-1.177 SBP 0.008 0.014 0.295 0.587 1.008 0.980-1.036 LDL-C 0.626 0.287 4.779 0.029 1.871 1.067-3.280 DBP 0.005 0.019 0.078 0.779 1.005 0.968-1.044 HDL-C −2.310 0.894 6.668 0.010 0.099 0.017-0.573 FGL 0.036 0.071 0.259 0.611 1.037 0.902-1.191 Apo A1 −3.363 1.263 7.085 0.008 0.035 0.003-0.412 BMI body mass index, TC total cholesterol, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, SBP systolic blood LDL-C low density lipoprotein cholesterol, HDL-C high density pressure, DBP diastolic blood pressure, FGL fasting glucose level lipoprotein cholesterol Wang et al. Lipids in Health and Disease (2018) 17:131 Page 6 of 7 suggesting increased LDL-C levels might be responsible measurement of ATT by the standardized method of digital radiography. ZAZ and MCF participated in the biochemical analysis. QZ and MJK analyzed for Achilles tendon thickening. We have also shown that the data and critically revised the manuscript. All authors read and approved those with borderline LDL-C levels had significantly the final manuscript. higher ATT compared with the normal LDL-C group. Ethics approval and consent to participate It has been shown that ATT is a clinical marker to This study was approved by the Ethical Committee, the Third People′sHospital identify patients at high risk for CVD . We found that of Hainan Province. All participants provided written informed consent. the serum LDL-C level was an independent risk factor, while HDL-C and Apo AI levels were protective factors, Consent for publication Participants were informed of data sharing with their name and identity for ATT. Therefore, LDL-C reduction would be import- hidden per consent. ant for the reduction of ATT and the risk of CVD. In- deed, the HMG CoA reductase inhibitor atorvastatin has Competing interests The authors declare that they have no competing interests. been shown to reduce ATT in patients with hyperchol- esterolemia  while treatment with simvastatin has been shown to result in regression of Achilles tendon Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in xanthomas . While effective in reducing low-density published maps and institutional affiliations. lipoprotein cholesterol levels and decreasing cardiovas- cular events, the use of HMG CoA reductase inhibitors Author details Department of Cardiology, the Third People′s Hospital of Hainan Province, can be limited due to patient intolerance from side 1154 Jiefang Road, Sanya 572000, Hainan, China. Division of Cardiology, effects. In that respect, nutraceuticals and functional Keenan Research Center for Biomedical Science at the Li Ka Shing food ingredients have been recommended as suitable Knowledge Institute, St. Michael′s Hospital, University of Toronto, Toronto, Ontario, Canada. Department of Radiology, the Third People′s Hospital of and amiable alternatives for control of dyslipidemia . Hainan Province, Sanya, Hainan, China. Department of Laboratory Medicine, For those patients with borderline LDL-C and those the Third People′s Hospital of Hainan Province, Sanya, Hainan, China. who simply do not prefer medications, nutraceuticals Received: 19 February 2018 Accepted: 3 May 2018 and functional food ingredients might be the preferred treatment choice. Limitations of this study include 1) the sample size is References small, limiting the generalizability of the results; and 2) 1. Kruth HS. Lipid deposition in human tendon xanthomas. Am J Pathol. 1985; 121:311–5. the study was carried out in a single center. Multi- 2. Hirobe K, Matsuzawa Y, Ishikawa K, Tarui S, Yamamoto A, Nambu S, et al. centered studies in large series are therefore needed to Coronary artery disease in heterozygous familial hypercholesterolemia. validate these findings. Atherosclerosis. 1982;44:201–10. 3. Ferrieres J, Lambert J, Lussier-Cacan S, Davignon J. 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Funding Guidelines for the management of familial hypercholesterolemia. J This study was supported partly by the Hainan Provincial Medical and Health Atheroscler Thromb. 2012;19:1043–60. Research Projects (1421320.24A1005). 9. Sugisawa T, Okamura T, Makino H, Watanabe M, Kishimoto I, Miyamoto Y, et al. Defining patients at extremely high risk for coronary artery Availability of data and materials disease in heterozygous familial hypercholesterolemia. J Atheroscler The authors declare that the data supporting the findings of this study are Thromb. 2012;19:369–75. available within the article. 10. Joint committee for developing Chinese guidelines on prevention and treatment of dyslipidemia in adults. Chinese guidelines on prevention and Authors’ contributions treatment of dyslipidemia in adults. Chin J Cardiol. 2007;35:390–419. BW prepared the figures and drafted the manuscript. LL designed the study 11. Descamps OS, Leysen X, Van Leuven F, Heller FR. 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