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Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention
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JJCC-1977; No. of Pages 5 Journal of Cardiology xxx (2019) xxx–xxx
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Original article
Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention Hideki Kitahara (MD PhD)*, Takashi Nakayama (MD PhD), Yoshihide Fujimoto (MD PhD), Yoshio Kobayashi (MD PhD FJCC) Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 August 2019 Received in revised form 20 December 2019 Accepted 1 January 2020 Available online xxx
Background: Tendon xanthoma, represented as Achilles tendon xanthoma (ATX), is one of the important diagnostic criteria for familial hypercholesterolemia (FH). However, there are some cases with ATX who do not meet these criteria. This study aimed to investigate the severity of coronary artery disease (CAD) in patients with ATX. Methods: A total of 394 patients with CAD undergoing percutaneous coronary intervention (PCI) at Chiba University Hospital between June 2016 and February 2018 were enrolled. Soft X-ray radiography of Achilles tendon was performed, and a maximum thickness of 9 mm or more was regarded as ATX. Heterozygous FH was diagnosed according to the diagnostic criteria proposed by the Japan Atherosclerosis Society in 2017. CAD severity was assessed by SYNTAX score before the first PCI during the study period. Results: There were 43 (10.9%) patients with ATX, and 16 (4.1%) were diagnosed as FH (15 with ATX and 1 without ATX). The ATX group showed greater body mass index, lower high-density lipoprotein cholesterol level, and the higher prevalence of FH, diabetes, prior myocardial infarction, acute coronary syndrome, multivessel disease, hemodialysis, and prior statin administration. SYNTAX score and the rate of SYNTAX score 23 were significantly higher in the ATX group compared with the non-ATX group (p < 0.001 for each). When patients were divided into quartiles according to Achilles tendon thickness, SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness (p < 0.001 for each). Multivariate analysis determined male, diabetes, and ATX as independent predictors for higher SYNTAX score. Conclusions: In CAD patients undergoing PCI, ATX was independently associated with severity of CAD. Detecting ATX may be useful not only for diagnosing FH, but also for identifying patients with advanced CAD. © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Coronary artery disease Familial hypercholesterolemia Achilles tendon xanthoma
Introduction Familial hypercholesterolemia (FH) is an autosomal dominant disorder with cholesterol elevation, especially a very high level of low-density lipoprotein (LDL) cholesterol, and the prevalence of its heterozygous form is reported to be 1 in 200–500 individuals [1–4]. Since FH leads to accelerated atherosclerosis and subsequent premature coronary artery disease (CAD) [5], early diagnosis and
* Corresponding author at: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 2608677, Japan. E-mail address: [email protected] (H. Kitahara).
optimal lipid-lowering therapy are essential. However, the majority of FH patients are reportedly underdiagnosed in many countries [6]. Tendon xanthoma, represented as Achilles tendon thickening, is one of the important diagnostic criteria for FH [7,8]. Although tendon xanthoma is well known to be highly specific for FH patients [9], there are some cases with Achilles tendon thickening who do not meet these criteria at a certain frequency [10–12]. One of the reasons for this phenomenon might be that FH can be masked by concurrent statin treatment, particularly in this era of more widespread prescribing of strong statins [13,14]. Tendon xanthoma is composed of monocyte-derived foam cells resulting from intracellular accumulation of lipids and connective tissue [15], and is generally dependent on the degree and duration of exposure to the elevated LDL-cholesterol level [16]. Therefore,
https://doi.org/10.1016/j.jjcc.2020.01.002 0914-5087/© 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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the presence of Achilles tendon xanthoma (ATX) itself might be one of the surrogate makers for development of atherosclerosis and CAD. Thus, the aim of this study was to investigate the severity of CAD in patients with ATX. Methods Study population The patients with CAD undergoing PCI at Chiba university hospital between June 2016 and February 2018 were enrolled in this study [17–20]. Among a total of consecutive 487 patients, 93 were excluded because of missing Achilles tendon thickness data, Achilles tendon thickening due to other reasons, such as sitosterolemia or a history of Achilles tendon rupture, and prior coronary artery bypass grafting (CABG), in which assessment of the severity of CAD using the SYNTAX score was difficult. Consequently, 394 patients were eligible for this analysis (Fig. 1). The institutional review boards at Chiba University Hospital approved this study, and all patients provided written informed consent. Measurement of Achilles tendon thickness In order to detect tendon xanthoma, soft X-ray radiography of the Achilles tendon was performed in all patients. A maximum thickness of 9 mm or more, excluding skin and subcutaneous tissue, was regarded as ATX according to the method in conformity with the guidelines proposed by the Japan Atherosclerosis Society (JAS) [8,21]. Measurements of Achilles tendon thickness in 40 randomly selected patients by 2 observers, and by 1 observer at 2 separate sessions, showed an interobserver correlation coefficient of 0.971 and an intraobserver coefficient of 0.985. Diagnosis of heterozygous FH Heterozygous FH was diagnosed, if a patient met two or three of the following criteria, according to the diagnostic criteria for heterozygous FH in adults proposed by JAS in 2017: (1) Hyper-LDL
cholesterolemia (an untreated LDL cholesterol level of >180 mg/ dL); (2) Tendon xanthomas (tendon xanthoma on backs of the hands, elbows, knees, or elsewhere, or Achilles tendon thickening) or xanthoma tuberosum; and (3) Family history of FH or premature CAD (within a patient’s 2nd degree relatives) [8]. In this study, genetic testing was not performed to identify monogenic mutations associated with FH. Plasma lipid levels were measured at hospital arrival before PCI in emergent PCI cases, and at hospital admission the day before PCI in elective PCI cases, regardless of food intake. If possible, previous data of lipid profiles before statin administration were obtained from medical records. LDL cholesterol level was usually measured by the direct method. However, if LDL cholesterol level was not available, it was calculated using the Friedewald equation. Evaluation of the severity of CAD CAD was categorized as stable CAD and acute coronary syndrome (ACS), which was further categorized as ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (NSTEACS) [22,23]. SYNTAX score was calculated using the SYNTAX score calculator (available at http://www.syntaxscore.com) based on the coronary angiography assessment before the first PCI during the study period. CAD severity was assessed by the total SYNTAX score composed of the individual scores for each separate lesion with a diameter stenosis of 50% in a vessel of 1.5 mm in diameter by visual assessment, as previously reported [24,25].
Statistical analysis Statistical analysis was performed using JMP1 10.0 (SAS Institute, Cary, NC, USA). Categorical variables are presented as numbers and percentages, and compared using chi-square test or Fisher’s exact test. Continuous variables are presented as mean SD. Comparisons of continuous variables between the two groups were done with a 2-tailed, unpaired t-test, and comparisons among the three groups were conducted using analysis of variance
Fig. 1. Patient population chart. ATX, Achilles tendon xanthoma; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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Table 1 Baseline clinical characteristics.
Age (years) Male BMI (kg/m2) Hypertension Dyslipidemia Familial hypercholesterolemia Diabetes Current smoker Family history of CAD Family history of premature CAD or FH Hemdialysis Prior myocardial infarction Prior PCI ACS STEMI NSTE-ACS Stable CAD Multivessel disease Number of PCI during the study period Left ventricular ejection fraction (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Prior statin administration Achilles tendon thickness (mm)
ATX (n = 43)
Non-ATX (n = 351)
p
67.9 8.6 35 (81.4%) 25.6 4.1 27 (62.8%) 33 (76.7%) 15 (34.9%) 24 (55.8%) 7 (16.3%) 16 (37.2%) 12 (27.9%) 5 (11.6%) 13 (30.2%) 18 (41.9%) 23 (53.5%) 8 (18.6%) 15 (34.9%) 20 (46.5%) 35 (81.4%) 1.1 0.4 54.3 13.7 185.5 57.5 118.3 49.8 47.7 16.9 136.4 87.2 29 (67.4%) 11.2 2.6
68.8 10.6 272 (77.5%) 24.1 3.6 254 (72.4%) 218 (62.1%) 1 (0.3%) 141 (40.2%) 60 (17.2%) 95 (27.9%) 16 (4.7%) 13 (3.7%) 48 (13.7%) 99 (28.2%) 117 (33.3%) 32 (9.1%) 85 (24.2%) 234 (66.7%) 125 (61.3%) 1.1 0.4 55.5 12.2 181.9 38.5 111.7 34.8 52.8 15.3 152.2 87.0 155 (44.2%) 6.7 0.8
0.620 0.560 0.012 0.190 0.060 <0.001 0.0497 0.875 0.207 <0.001 0.019 0.005 0.064 0.009 0.023
0.010 0.887 0.547 0.593 0.282 0.048 0.263 0.004 <0.001
ACS, acute coronary syndrome; ATX, Achilles tendon xanthoma; BMI, body mass index; CAD, coronary artery disease; FH, familial hypercholesterolemia; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; NSTE-ACS, non ST-elevation-ACS; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
(ANOVA). A nominal p-value of <0.05 was considered statistically significant. Forward stepwise multivariate logistic regression models were used to determine independent predictors of intermediate-high SYNTAX score (23). The variables with pvalue <0.05 in univariate models were included simultaneously in multivariate models. The variables, which were strongly correlated with SYNTAX score, such as number of PCI during the study period and multivessel disease, were excluded in multivariate models. Results In a total of 394 patients, median (interquartile range) of Achilles tendon thickness was 6.8 (6.2–7.5) mm. ATX was observed in 43 (10.9%) patients, and 16 (4.1%) patients were diagnosed as heterozygous FH (15 with ATX and 1 without ATX). Baseline clinical characteristics were compared between the ATX and non-ATX groups (Table 1). The ATX group showed greater body mass index, and a higher prevalence of FH, diabetes, family history of premature CAD or FH, prior myocardial infarction, multivessel disease, hemodialysis, and prior statin administration. Regarding clinical presentation at the first PCI during the study period, ACS was more frequent in the ATX group compared with the non-ATX group. In terms of lipid profiles, high-density lipoprotein cholesterol level was significantly lower in the ATX group compared with the non-ATX group. Overall, the mean SYNTAX score was 13.7 8.3, and 53 patients (13.5%) had intermediate-high SYNTAX score (23). The ATX group demonstrated significantly higher SYNTAX score and higher prevalence of SYNTAX score 23 compared with the non-ATX group (p < 0.001 for each) (Fig. 2). In comparison of FH patients (n = 16), non-FH patients with ATX (n = 28), and control patients (n = 350), SYNTAX score was significantly higher in both FH and non-FH patients with ATX compared with control patients (19.9 11.7 vs. 22.6 7.3 vs. 12.7 7.6, p < 0.001), and the prevalence of SYNTAX score 23 was the highest in non-FH patients with ATX among the 3 groups (31.3% vs. 50.0% vs. 9.7%, p < 0.001). When
Fig. 2. Comparison of SYNTAX score and the prevalence of SYNTAX score 23 between the ATX and non-ATX groups. Both SYNTAX score and the prevalence of SYNTAX score 23 were significantly higher in the ATX group compared with the non-ATX group. ATX, Achilles tendon xanthoma.
patients were divided into quartiles according to Achilles tendon thickness: Quartile 1 (Q1) <6.2 mm, Q2 6.2–6.8 mm, Q3 6.8–7.5 mm, and Q4 >7.5 mm, SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness (p < 0.001 for each) (Fig. 3). From the results of multivariate logistic regression analysis, male, diabetes, and ATX were independent predictors for SYNTAX score 23 (Table 2). Discussion The present study demonstrated that the ATX group showed higher SYNTAX score compared with the non-ATX group. Furthermore, the greater Achilles tendon thickness was, the more
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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Fig. 3. Comparison of SYNTAX score and the prevalence of SYNTAX score 23 among quartile subgroups of Achilles tendon thickness. Both SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness. Quartile 1 (Q1): Achilles tendon thickness <6.2 mm, Q2: 6.2–6.8 mm, Q3: 6.8–7.5 mm, Q4: >7.5 mm.
SYNTAX score was increased. Multivariate analysis showed the significant association of ATX, as well as male and diabetes, with higher SYNTAX score. Thus, the presence of ATX itself may be an independent predictor for severity of CAD. Xanthomas are grayish-yellow to yellow masses composed of broad sheets or thick columns of xanthoma cells (lipid-filled foamy histiocytes), as well as extracellular cholesterol (cholesterol clefts), giant cells, and scattered inflammatory cells interspersed between tendon fascicles [26,27]. Although the mechanism of xanthoma production is not fully known, it is likely that its formation is dependent on the degree and duration of exposure to the elevated LDL cholesterol level in most cases [16]. Tendon xanthoma can be seen in various parts of the body, such as dorsal hands, elbows, knees, or Achilles tendon. Of these, only ATX can be quantitatively evaluated by measuring tendon thickness with soft X-ray radiography, ultrasonography, or magnetic resonance imaging [28]. Thus, identifying ATX plays an important role for diagnosis of FH [8]. Recently, a pilot study reported the association of ATX with
the extension of subclinical coronary atherosclerosis quantified by computed tomographic calcium scoring in FH patients [29]. However, little has been known about the relationship between ATX and angiographic severity and extent of CAD even in FH patients. It has been previously reported that approximately 70% of patients with ATX are not clinically diagnosed as having FH [10– 12]. In the present study, 65.1% of patients with ATX (7.1% of all patients) did not fulfill the diagnostic criteria of heterozygous FH. There is a possibility that such patients could be diagnosed as having FH through genetic testing largely, because widespread use of strong statin therapy can mask elevation of serum cholesterol in FH patients. Furthermore, in ACS patients, LDL cholesterol level is reportedly decreased after the onset of ACS and remains low for several weeks [30]. In addition, the inflammatory factors in ACS patients would relate to the decrease in LDL cholesterol [31]. Regarding family history of FH or premature CAD, it is sometimes difficult to collect all pertinent health information from patients’ relatives. Although genetic testing would be useful to clarify diagnosis of FH in such patients, it is costly and impractical in common clinical settings. Another possibility explaining the presence of clinically non-FH patients with ATX is that non-FH dyslipidemic patients without genetic abnormality might be able to have ATX. However, further investigation is warranted to clarify this issue. Despite the existence of FH, dyslipidemia is associated with development of CAD. However, LDL cholesterol level can fluctuate and/or be masked by medical therapy. While long-term exposure to elevated LDL cholesterol level may be associated with development of CAD, arbitrary measurements of LDL cholesterol level might be insufficient to precisely evaluate the degree of dyslipidemia or FH. In the present study, FH patients and non-FH patients with ATX had similar development of CAD. Since the association of FH with the development of CAD is clearly recognized, patients diagnosed with FH usually receive careful treatment and extensive lipid-lowering therapy. On the other hand, non-FH patients might have insufficient medical therapy for preventing CAD. By detecting ATX, it may be an invaluable tool to identify high-risk patients requiring adequate medical therapy, and estimate the severity of CAD.
Table 2 Univariate and multivariate logistic regression analyses of the variables associated with SYNTAX score 23. Univariate analysis
Age Male BMI Hypertension Dyslipidemia Familial hypercholesterolemia Diabetes Current smoker Family history of CAD Family history of premature CAD or FH Prior myocardial infarction Prior PCI ACS Hemodialysis Left ventricular ejection fraction Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Prior statin administration ATX group
Multivariate analysis
OR
95% CI
p-Value
1.005 3.039 1.004 1.277 1.695 3.125 2.869 1.319 1.355 2.884 1.322 1.386 1.468 3.500 0.977 0.997 0.997 0.978 0.998 1.731 7.381
0.977–1.034 1.280–8.976 0.927–1.084 0.671–2.576 0.905–3.344 0.951–8.999 1.587–5.326 0.614–2.640 0.717–2.491 1.136–6.745 0.596–2.707 0.743–2.523 0.809–2.634 1.172–9.476 0.956–1.000 0.989–1.004 0.988–1.005 0.956–0.998 0.994–1.001 0.968–3.145 3.656–14.870
0.728 0.010 0.916 0.467 0.101 0.060 <0.001 0.462 0.342 0.027 0.474 0.299 0.204 0.027 0.050 0.337 0.451 0.034 0.259 0.065 <0.001
OR
95% CI
p-Value
2.618
1.025–8.149
0.044
2.370
1.211–4.737
0.012
1.598
0.501–4.583
0.412
1.443
0.343–5.112
0.598
0.994
0.970–1.016
0.573
6.306
2.827–14.048
<0.001
ACS, acute coronary syndrome; ATX, Achilles tendon xanthoma; BMI, body mass index; CAD, coronary artery disease; FH, familial hypercholesterolemia; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; PCI, percutaneous coronary intervention.
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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There were several limitations in the present study. First, sample size was relatively small, especially in FH and non-FH patients with ATX. Second, untreated LDL cholesterol level was unknown in some patients on statin therapy. Third, patients with prior CABG, who should have severe CAD, were excluded. Fourth, genetic molecular analysis was not performed to identify monogenic mutations associated with FH. Therefore, it was unclear how many patients with ATX who did not meet the clinical diagnostic criteria for heterozygous FH were genetically diagnosed as having FH. Fifth, it has also been reported that FH patients with genetic diagnosis do not have ATX at a certain rate (20%–30%) [32,33]. Thus, the absence of ATX should not lead to exclusion of genetic FH diagnosis with advanced CAD. Conclusions
[10]
[11]
[12]
[13] [14]
[15] [16]
In CAD patients undergoing PCI, ATX was independently associated with severity of CAD despite the presence of clinically diagnosed FH. Detecting ATX may be useful not only for diagnosing FH, but also for identifying patients with advanced CAD.
[17]
[18]
Funding This research received no payment/grant from any funding agency for manuscript preparation.
[19]
Conflict of interest
[20]
All authors report no conflict of interest related to this study. [21]
Acknowledgment [22]
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Original article
Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention Hideki Kitahara (MD PhD)*, Takashi Nakayama (MD PhD), Yoshihide Fujimoto (MD PhD), Yoshio Kobayashi (MD PhD FJCC) Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 August 2019 Received in revised form 20 December 2019 Accepted 1 January 2020 Available online xxx
Background: Tendon xanthoma, represented as Achilles tendon xanthoma (ATX), is one of the important diagnostic criteria for familial hypercholesterolemia (FH). However, there are some cases with ATX who do not meet these criteria. This study aimed to investigate the severity of coronary artery disease (CAD) in patients with ATX. Methods: A total of 394 patients with CAD undergoing percutaneous coronary intervention (PCI) at Chiba University Hospital between June 2016 and February 2018 were enrolled. Soft X-ray radiography of Achilles tendon was performed, and a maximum thickness of 9 mm or more was regarded as ATX. Heterozygous FH was diagnosed according to the diagnostic criteria proposed by the Japan Atherosclerosis Society in 2017. CAD severity was assessed by SYNTAX score before the first PCI during the study period. Results: There were 43 (10.9%) patients with ATX, and 16 (4.1%) were diagnosed as FH (15 with ATX and 1 without ATX). The ATX group showed greater body mass index, lower high-density lipoprotein cholesterol level, and the higher prevalence of FH, diabetes, prior myocardial infarction, acute coronary syndrome, multivessel disease, hemodialysis, and prior statin administration. SYNTAX score and the rate of SYNTAX score 23 were significantly higher in the ATX group compared with the non-ATX group (p < 0.001 for each). When patients were divided into quartiles according to Achilles tendon thickness, SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness (p < 0.001 for each). Multivariate analysis determined male, diabetes, and ATX as independent predictors for higher SYNTAX score. Conclusions: In CAD patients undergoing PCI, ATX was independently associated with severity of CAD. Detecting ATX may be useful not only for diagnosing FH, but also for identifying patients with advanced CAD. © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Coronary artery disease Familial hypercholesterolemia Achilles tendon xanthoma
Introduction Familial hypercholesterolemia (FH) is an autosomal dominant disorder with cholesterol elevation, especially a very high level of low-density lipoprotein (LDL) cholesterol, and the prevalence of its heterozygous form is reported to be 1 in 200–500 individuals [1–4]. Since FH leads to accelerated atherosclerosis and subsequent premature coronary artery disease (CAD) [5], early diagnosis and
* Corresponding author at: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 2608677, Japan. E-mail address: [email protected] (H. Kitahara).
optimal lipid-lowering therapy are essential. However, the majority of FH patients are reportedly underdiagnosed in many countries [6]. Tendon xanthoma, represented as Achilles tendon thickening, is one of the important diagnostic criteria for FH [7,8]. Although tendon xanthoma is well known to be highly specific for FH patients [9], there are some cases with Achilles tendon thickening who do not meet these criteria at a certain frequency [10–12]. One of the reasons for this phenomenon might be that FH can be masked by concurrent statin treatment, particularly in this era of more widespread prescribing of strong statins [13,14]. Tendon xanthoma is composed of monocyte-derived foam cells resulting from intracellular accumulation of lipids and connective tissue [15], and is generally dependent on the degree and duration of exposure to the elevated LDL-cholesterol level [16]. Therefore,
https://doi.org/10.1016/j.jjcc.2020.01.002 0914-5087/© 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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the presence of Achilles tendon xanthoma (ATX) itself might be one of the surrogate makers for development of atherosclerosis and CAD. Thus, the aim of this study was to investigate the severity of CAD in patients with ATX. Methods Study population The patients with CAD undergoing PCI at Chiba university hospital between June 2016 and February 2018 were enrolled in this study [17–20]. Among a total of consecutive 487 patients, 93 were excluded because of missing Achilles tendon thickness data, Achilles tendon thickening due to other reasons, such as sitosterolemia or a history of Achilles tendon rupture, and prior coronary artery bypass grafting (CABG), in which assessment of the severity of CAD using the SYNTAX score was difficult. Consequently, 394 patients were eligible for this analysis (Fig. 1). The institutional review boards at Chiba University Hospital approved this study, and all patients provided written informed consent. Measurement of Achilles tendon thickness In order to detect tendon xanthoma, soft X-ray radiography of the Achilles tendon was performed in all patients. A maximum thickness of 9 mm or more, excluding skin and subcutaneous tissue, was regarded as ATX according to the method in conformity with the guidelines proposed by the Japan Atherosclerosis Society (JAS) [8,21]. Measurements of Achilles tendon thickness in 40 randomly selected patients by 2 observers, and by 1 observer at 2 separate sessions, showed an interobserver correlation coefficient of 0.971 and an intraobserver coefficient of 0.985. Diagnosis of heterozygous FH Heterozygous FH was diagnosed, if a patient met two or three of the following criteria, according to the diagnostic criteria for heterozygous FH in adults proposed by JAS in 2017: (1) Hyper-LDL
cholesterolemia (an untreated LDL cholesterol level of >180 mg/ dL); (2) Tendon xanthomas (tendon xanthoma on backs of the hands, elbows, knees, or elsewhere, or Achilles tendon thickening) or xanthoma tuberosum; and (3) Family history of FH or premature CAD (within a patient’s 2nd degree relatives) [8]. In this study, genetic testing was not performed to identify monogenic mutations associated with FH. Plasma lipid levels were measured at hospital arrival before PCI in emergent PCI cases, and at hospital admission the day before PCI in elective PCI cases, regardless of food intake. If possible, previous data of lipid profiles before statin administration were obtained from medical records. LDL cholesterol level was usually measured by the direct method. However, if LDL cholesterol level was not available, it was calculated using the Friedewald equation. Evaluation of the severity of CAD CAD was categorized as stable CAD and acute coronary syndrome (ACS), which was further categorized as ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (NSTEACS) [22,23]. SYNTAX score was calculated using the SYNTAX score calculator (available at http://www.syntaxscore.com) based on the coronary angiography assessment before the first PCI during the study period. CAD severity was assessed by the total SYNTAX score composed of the individual scores for each separate lesion with a diameter stenosis of 50% in a vessel of 1.5 mm in diameter by visual assessment, as previously reported [24,25].
Statistical analysis Statistical analysis was performed using JMP1 10.0 (SAS Institute, Cary, NC, USA). Categorical variables are presented as numbers and percentages, and compared using chi-square test or Fisher’s exact test. Continuous variables are presented as mean SD. Comparisons of continuous variables between the two groups were done with a 2-tailed, unpaired t-test, and comparisons among the three groups were conducted using analysis of variance
Fig. 1. Patient population chart. ATX, Achilles tendon xanthoma; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.
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Table 1 Baseline clinical characteristics.
Age (years) Male BMI (kg/m2) Hypertension Dyslipidemia Familial hypercholesterolemia Diabetes Current smoker Family history of CAD Family history of premature CAD or FH Hemdialysis Prior myocardial infarction Prior PCI ACS STEMI NSTE-ACS Stable CAD Multivessel disease Number of PCI during the study period Left ventricular ejection fraction (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Prior statin administration Achilles tendon thickness (mm)
ATX (n = 43)
Non-ATX (n = 351)
p
67.9 8.6 35 (81.4%) 25.6 4.1 27 (62.8%) 33 (76.7%) 15 (34.9%) 24 (55.8%) 7 (16.3%) 16 (37.2%) 12 (27.9%) 5 (11.6%) 13 (30.2%) 18 (41.9%) 23 (53.5%) 8 (18.6%) 15 (34.9%) 20 (46.5%) 35 (81.4%) 1.1 0.4 54.3 13.7 185.5 57.5 118.3 49.8 47.7 16.9 136.4 87.2 29 (67.4%) 11.2 2.6
68.8 10.6 272 (77.5%) 24.1 3.6 254 (72.4%) 218 (62.1%) 1 (0.3%) 141 (40.2%) 60 (17.2%) 95 (27.9%) 16 (4.7%) 13 (3.7%) 48 (13.7%) 99 (28.2%) 117 (33.3%) 32 (9.1%) 85 (24.2%) 234 (66.7%) 125 (61.3%) 1.1 0.4 55.5 12.2 181.9 38.5 111.7 34.8 52.8 15.3 152.2 87.0 155 (44.2%) 6.7 0.8
0.620 0.560 0.012 0.190 0.060 <0.001 0.0497 0.875 0.207 <0.001 0.019 0.005 0.064 0.009 0.023
0.010 0.887 0.547 0.593 0.282 0.048 0.263 0.004 <0.001
ACS, acute coronary syndrome; ATX, Achilles tendon xanthoma; BMI, body mass index; CAD, coronary artery disease; FH, familial hypercholesterolemia; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; NSTE-ACS, non ST-elevation-ACS; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
(ANOVA). A nominal p-value of <0.05 was considered statistically significant. Forward stepwise multivariate logistic regression models were used to determine independent predictors of intermediate-high SYNTAX score (23). The variables with pvalue <0.05 in univariate models were included simultaneously in multivariate models. The variables, which were strongly correlated with SYNTAX score, such as number of PCI during the study period and multivessel disease, were excluded in multivariate models. Results In a total of 394 patients, median (interquartile range) of Achilles tendon thickness was 6.8 (6.2–7.5) mm. ATX was observed in 43 (10.9%) patients, and 16 (4.1%) patients were diagnosed as heterozygous FH (15 with ATX and 1 without ATX). Baseline clinical characteristics were compared between the ATX and non-ATX groups (Table 1). The ATX group showed greater body mass index, and a higher prevalence of FH, diabetes, family history of premature CAD or FH, prior myocardial infarction, multivessel disease, hemodialysis, and prior statin administration. Regarding clinical presentation at the first PCI during the study period, ACS was more frequent in the ATX group compared with the non-ATX group. In terms of lipid profiles, high-density lipoprotein cholesterol level was significantly lower in the ATX group compared with the non-ATX group. Overall, the mean SYNTAX score was 13.7 8.3, and 53 patients (13.5%) had intermediate-high SYNTAX score (23). The ATX group demonstrated significantly higher SYNTAX score and higher prevalence of SYNTAX score 23 compared with the non-ATX group (p < 0.001 for each) (Fig. 2). In comparison of FH patients (n = 16), non-FH patients with ATX (n = 28), and control patients (n = 350), SYNTAX score was significantly higher in both FH and non-FH patients with ATX compared with control patients (19.9 11.7 vs. 22.6 7.3 vs. 12.7 7.6, p < 0.001), and the prevalence of SYNTAX score 23 was the highest in non-FH patients with ATX among the 3 groups (31.3% vs. 50.0% vs. 9.7%, p < 0.001). When
Fig. 2. Comparison of SYNTAX score and the prevalence of SYNTAX score 23 between the ATX and non-ATX groups. Both SYNTAX score and the prevalence of SYNTAX score 23 were significantly higher in the ATX group compared with the non-ATX group. ATX, Achilles tendon xanthoma.
patients were divided into quartiles according to Achilles tendon thickness: Quartile 1 (Q1) <6.2 mm, Q2 6.2–6.8 mm, Q3 6.8–7.5 mm, and Q4 >7.5 mm, SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness (p < 0.001 for each) (Fig. 3). From the results of multivariate logistic regression analysis, male, diabetes, and ATX were independent predictors for SYNTAX score 23 (Table 2). Discussion The present study demonstrated that the ATX group showed higher SYNTAX score compared with the non-ATX group. Furthermore, the greater Achilles tendon thickness was, the more
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Fig. 3. Comparison of SYNTAX score and the prevalence of SYNTAX score 23 among quartile subgroups of Achilles tendon thickness. Both SYNTAX score and the prevalence of SYNTAX score 23 were progressively increased in favor of greater Achilles tendon thickness. Quartile 1 (Q1): Achilles tendon thickness <6.2 mm, Q2: 6.2–6.8 mm, Q3: 6.8–7.5 mm, Q4: >7.5 mm.
SYNTAX score was increased. Multivariate analysis showed the significant association of ATX, as well as male and diabetes, with higher SYNTAX score. Thus, the presence of ATX itself may be an independent predictor for severity of CAD. Xanthomas are grayish-yellow to yellow masses composed of broad sheets or thick columns of xanthoma cells (lipid-filled foamy histiocytes), as well as extracellular cholesterol (cholesterol clefts), giant cells, and scattered inflammatory cells interspersed between tendon fascicles [26,27]. Although the mechanism of xanthoma production is not fully known, it is likely that its formation is dependent on the degree and duration of exposure to the elevated LDL cholesterol level in most cases [16]. Tendon xanthoma can be seen in various parts of the body, such as dorsal hands, elbows, knees, or Achilles tendon. Of these, only ATX can be quantitatively evaluated by measuring tendon thickness with soft X-ray radiography, ultrasonography, or magnetic resonance imaging [28]. Thus, identifying ATX plays an important role for diagnosis of FH [8]. Recently, a pilot study reported the association of ATX with
the extension of subclinical coronary atherosclerosis quantified by computed tomographic calcium scoring in FH patients [29]. However, little has been known about the relationship between ATX and angiographic severity and extent of CAD even in FH patients. It has been previously reported that approximately 70% of patients with ATX are not clinically diagnosed as having FH [10– 12]. In the present study, 65.1% of patients with ATX (7.1% of all patients) did not fulfill the diagnostic criteria of heterozygous FH. There is a possibility that such patients could be diagnosed as having FH through genetic testing largely, because widespread use of strong statin therapy can mask elevation of serum cholesterol in FH patients. Furthermore, in ACS patients, LDL cholesterol level is reportedly decreased after the onset of ACS and remains low for several weeks [30]. In addition, the inflammatory factors in ACS patients would relate to the decrease in LDL cholesterol [31]. Regarding family history of FH or premature CAD, it is sometimes difficult to collect all pertinent health information from patients’ relatives. Although genetic testing would be useful to clarify diagnosis of FH in such patients, it is costly and impractical in common clinical settings. Another possibility explaining the presence of clinically non-FH patients with ATX is that non-FH dyslipidemic patients without genetic abnormality might be able to have ATX. However, further investigation is warranted to clarify this issue. Despite the existence of FH, dyslipidemia is associated with development of CAD. However, LDL cholesterol level can fluctuate and/or be masked by medical therapy. While long-term exposure to elevated LDL cholesterol level may be associated with development of CAD, arbitrary measurements of LDL cholesterol level might be insufficient to precisely evaluate the degree of dyslipidemia or FH. In the present study, FH patients and non-FH patients with ATX had similar development of CAD. Since the association of FH with the development of CAD is clearly recognized, patients diagnosed with FH usually receive careful treatment and extensive lipid-lowering therapy. On the other hand, non-FH patients might have insufficient medical therapy for preventing CAD. By detecting ATX, it may be an invaluable tool to identify high-risk patients requiring adequate medical therapy, and estimate the severity of CAD.
Table 2 Univariate and multivariate logistic regression analyses of the variables associated with SYNTAX score 23. Univariate analysis
Age Male BMI Hypertension Dyslipidemia Familial hypercholesterolemia Diabetes Current smoker Family history of CAD Family history of premature CAD or FH Prior myocardial infarction Prior PCI ACS Hemodialysis Left ventricular ejection fraction Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Prior statin administration ATX group
Multivariate analysis
OR
95% CI
p-Value
1.005 3.039 1.004 1.277 1.695 3.125 2.869 1.319 1.355 2.884 1.322 1.386 1.468 3.500 0.977 0.997 0.997 0.978 0.998 1.731 7.381
0.977–1.034 1.280–8.976 0.927–1.084 0.671–2.576 0.905–3.344 0.951–8.999 1.587–5.326 0.614–2.640 0.717–2.491 1.136–6.745 0.596–2.707 0.743–2.523 0.809–2.634 1.172–9.476 0.956–1.000 0.989–1.004 0.988–1.005 0.956–0.998 0.994–1.001 0.968–3.145 3.656–14.870
0.728 0.010 0.916 0.467 0.101 0.060 <0.001 0.462 0.342 0.027 0.474 0.299 0.204 0.027 0.050 0.337 0.451 0.034 0.259 0.065 <0.001
OR
95% CI
p-Value
2.618
1.025–8.149
0.044
2.370
1.211–4.737
0.012
1.598
0.501–4.583
0.412
1.443
0.343–5.112
0.598
0.994
0.970–1.016
0.573
6.306
2.827–14.048
<0.001
ACS, acute coronary syndrome; ATX, Achilles tendon xanthoma; BMI, body mass index; CAD, coronary artery disease; FH, familial hypercholesterolemia; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; PCI, percutaneous coronary intervention.
Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002
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There were several limitations in the present study. First, sample size was relatively small, especially in FH and non-FH patients with ATX. Second, untreated LDL cholesterol level was unknown in some patients on statin therapy. Third, patients with prior CABG, who should have severe CAD, were excluded. Fourth, genetic molecular analysis was not performed to identify monogenic mutations associated with FH. Therefore, it was unclear how many patients with ATX who did not meet the clinical diagnostic criteria for heterozygous FH were genetically diagnosed as having FH. Fifth, it has also been reported that FH patients with genetic diagnosis do not have ATX at a certain rate (20%–30%) [32,33]. Thus, the absence of ATX should not lead to exclusion of genetic FH diagnosis with advanced CAD. Conclusions
[10]
[11]
[12]
[13] [14]
[15] [16]
In CAD patients undergoing PCI, ATX was independently associated with severity of CAD despite the presence of clinically diagnosed FH. Detecting ATX may be useful not only for diagnosing FH, but also for identifying patients with advanced CAD.
[17]
[18]
Funding This research received no payment/grant from any funding agency for manuscript preparation.
[19]
Conflict of interest
[20]
All authors report no conflict of interest related to this study. [21]
Acknowledgment [22]
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Please cite this article in press as: Kitahara H, et al. Association between Achilles tendon xanthoma and severity of coronary artery disease in patients undergoing percutaneous coronary intervention. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2020.01.002