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Achilles tendon thickening is associated with disease severity and plaque vulnerability in patients with coronary artery disease
Journal of Clinical Lipidology (2018) -, -–-
Original Article
Achilles tendon thickening is associated with disease severity and plaque vulnerability in patients with coronary artery disease Takuya Hashimoto, MD, Yoshiyasu Minami, MD, PhD*, Ryota Kakizaki, MD, Teruyoshi Nemoto, MD, Kazuhiro Fujiyoshi, MD, Kentaro Meguro, MD, PhD, Takao Shimohama, MD, PhD, Taiki Tojo, MD, PhD, Junya Ako, MD, PhD Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan (Drs Hashimoto, Kakizaki, Nemoto, Fujiyoshi, and Ako); and Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan (Drs Minami, Meguro, Shimohama, Tojo, and Ako) KEYWORDS: Familial hypercholesterolemia; Optical coherence tomography; Vulnerable plaque; Dyslipidemia; Multivessel disease
BACKGROUND: Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters and a marker of high risk for coronary artery disease (CAD). OBJECTIVE: The aim of the article was to clarify whether the presence of Achilles tendon thickening (ATT) was associated with disease severity and plaque vulnerability in patients with CAD. METHODS: A total of 241 consecutive patients who underwent percutaneous coronary intervention and ATT assessment were analyzed. ATT was defined as Achilles tendon thickness of $9 mm on radiograph. The severity of CAD and plaque vulnerability was assessed by the findings on angiogram and optical coherence tomography, respectively. RESULTS: ATT was found in 44 patients (18.2%). The frequency of multivessel disease (79.6% vs 58.4%, P 5 .009) and left main lesion (13.6% vs 3.1%, P 5 .004) was significantly higher in patients with ATT (ATT group) than in patients without ATT (no ATT group). Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (odds ratio, 2.33; 95% confidence interval, 1.08–5.46; P 5 .031). The ATT group had a higher prevalence of intimal vascular channels (50.0% vs 24.7%, P 5 .018) and macrophage accumulation (58.3% vs 33.3%, P 5 .028) in culprit plaque than the no ATT group. CONCLUSIONS: Patients with the presence of ATT had a higher prevalence of multivessel coronary disease and left main coronary artery disease than with patients without ATT. The presence of ATT was also associated with vulnerable features, including intimal vascular channels and macrophage accumulation in culprit plaques. Ó 2018 National Lipid Association. All rights reserved.
Introduction * Corresponding author. Department of Cardiovascular Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. E-mail address: [email protected] Submitted May 26, 2018. Accepted for publication October 19, 2018.
1933-2874/Ó 2018 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2018.10.007
Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters.1 Among tendon xanthomas in upper/lower limbs, Achilles tendon xanthomas are the most objective finding because Achilles tendon thickening (ATT) can be quantitatively evaluable on
2 radiography. Although the precise pathophysiology of Achilles tendon xanthomas is still unclear, a recent study reported that a strong positive correlation was observed between Achilles tendon thickness and cholesterol-year score, which is calculated by the age and the mean serum cholesterol concentration of the patients.2 In addition, several previous studies have demonstrated that patients with tendon xanthomas had a higher risk of coronary artery disease (CAD) than those without tendon xanthomas.3,4 Recently, Tada et al. reported that patients with clinical signs of familial hypercholesterolemia (FH; xanthomas and/or family history) or FH gene mutation had 4.6-fold higher odds of developing CAD than those without clinical signs or gene mutation among patients with significantly elevated lowdensity lipoprotein (LDL) cholesterol levels.5 Thus, the presence of ATT may be an indicator of advanced atherosclerosis and/or vulnerable plaque. In the present study, we aimed to clarify whether the presence of ATT was associated with disease severity and plaque vulnerability in patients with CAD.
Methods A total of 296 consecutive patients underwent percutaneous coronary intervention (PCI) at our institution between June 2016 and March 2017. Among them, 241 patients with the measurement of Achilles tendon thickness were enrolled in the present study (Supplemental Fig. 1). Achilles tendon thickness was measured by radiography during hospitalization. The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the ethics committees of our institution. Achilles tendon thickness was measured by soft x-ray radiography according to the recommended method in a guideline (Supplemental Fig. 2).6 In brief, radiograms were taken with each ankle placed lateral side down on the film and the foot flexed at 90 . The anteroposterior diameter of both Achilles tendons was measured at the point of maximal thickening of the tendon except subcutaneous tissue. ATT was defined as the maximum Achilles tendon thickness of $9 mm. The laboratory findings were obtained on admission. Dyslipidemia was defined as LDL cholesterol levels .140 mg/dL and/or use of lipid-lowering drugs. To diagnose FH, baseline LDL cholesterol levels before a prescribed lipid-lowering drugs were additionally collected from hospital record. If baseline values of LDL cholesterol before treatment were not available, we estimated the baseline value with an approximate reduction of LDL cholesterol by 30%.7 A family history of CAD was defined as positive by a first-degree family member having CAD. The diagnosis of FH was based on a modified form of the Dutch Lipid Clinic Network criteria, in which the diagnosis of Achilles tendon xanthoma is based on radiographic criteria rather than physical examination.8 The severity of CAD was assessed by coronary angiography findings. Left main (LM) lesion was defined as a reduction of at least
Journal of Clinical Lipidology, Vol -, No -, - 2018 50% in the luminal diameter of the LM. Multivessel disease was defined as $70% stenosis and/or PCI history in at least one other epicardial coronary artery in addition to culprit artery. Optical coherence tomography (OCT) imaging of culprit lesion was performed in 128 patients. Among them, 105 patients were included in the OCT analysis after excluding 23 patients with poor image quality (n 5 7) or in-stent restenosis (n 5 16). OCT images were acquired using frequency domain OCT (C7-XR Intravascular Imaging System; St Jude Medical, Inc, St Paul, MN) after intracoronary administration of 100 to 200 mg of nitroglycerin. All images were analyzed using offline proprietary software (St Jude Medical). Qualitative and quantitative analyses were performed at 1 mm intervals. All OCT plaque morphologies were assessed according to international consensus standards for intravascular OCT studies.9,10 Fibrous cap thickness was measured at its thinnest part 3 times, and the average value was calculated. Thin-cap fibroatheroma (TCFA) was defined as a lipid plaque with lipid arc .90 and the thickness of fibrous cap ,65 mm. The presence of bright spots within the fibrous cap with backward shadowing was considered indicative of macrophage accumulation.10 Intimal vascular channels were defined as small black holes or tubular structures of 50 to 100 mm diameter that were present within a plaque on at least 3 consecutive cross-sectional frames.10,11 Cholesterol crystals were defined as thin and linear regions of high light intensity without signal attenuation.12 Calcifications were defined as signal-poor or heterogeneous areas delimited by sharp borders. Calcified lesions subtending an arc ,90 and extending in length for 1 to 4 mm were classified as spotty calcium.13 Thrombus was defined as a mass .250 mm attached to the luminal surface or floating within the lumen.10,14 Continuous variables are expressed as mean 6 standard deviation and compared using the unpaired t-test or the Wilcoxon rank-sum test. Categorical variables are presented as numbers and frequencies and compared using the chi-square test. A univariate logistic regression model was used to assess the predictor of multivessel disease and LM trunk lesion. Multivariate logistic regression models were further used to assess the predictor of
Figure 1
Distribution of Achilles tendon thickness.
Hashimoto et al Table 1
Achilles tendon thickening and coronary disease
3
Baseline characteristics
Demographic characteristics Age, y Male gender, n (%) BMI Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Current smoker, n (%) Chronic kidney disease, n (%) Family history of CAD, n (%) Previous MI, n (%) Previous PCI, n (%) Previous CABG, n (%) Laboratory findings LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL Hemoglobin A1c, % eGFR, mL/min/1.73 m2 BNP, pg/mL Medications Statin, n (%) Ezetimibe, n (%)
ATT (1) (N 5 44)
ATT (2) (N 5 197)
P value
66.0 6 10.4 40 (90.9) 24.6 6 3.2 36 (81.8) 36 (81.8) 22 (50.0) 7 (15.9) 29 (65.9) 15 (34.1) 16 (36.4) 21 (47.7) 2 (4.6)
69.3 6 10.7 152 (77.2) 24.1 6 3.5 150 (76.1) 134 (68.0) 83 (42.1) 47 (23.9) 96 (48.7) 50 (25.4) 54 (27.4) 59 (30.0) 4 (2.0)
.068 .040 .424 .417 .070 .341 0.253 .039 .239 .237 .024 .333
99.7 6 33.7 47.6 6 12.4 177.1 6 118.5 6.4 6 1.7 49.7 6 24.5 87.3 (38.3–166.5)
104.6 6 38.3 50.9 6 13.9 150.4 6 104.9 6.5 6 0.1 59.1 6 20.1 72.3 (29.2–188.0)
.447 .149 .141 .614 .007 .742
36 (81.8) 6 (13.6)
117 (59.4) 11 (5.6)
.005 .059
ATT, Achilles tendon thickening; BMI, body mass index; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention. Bold values represent P values with statistical significance (,.05).
multivessel disease. We included the factors with P , .05 and those with P , .10 in univariate logistic regression model into the model 1 and model 2, respectively. A P value , .05 was used to indicate statistical significance. All analyses were performed using JMP version 12.0.1 for Windows (SAS, NC).
Results Mean Achilles tendon thickness was 7.9 6 1.6 mm. ATT was found in 44 patients (18.2%; Fig. 1). Baseline characteristics according to the presence of ATT are shown in Table 2
Table 1. The prevalence of males was higher in the ATT group than in the no ATT group. ATT was associated with higher prevalence of chronic kidney disease and history of PCI. There were no significant differences in LDL cholesterol levels between the 2 groups, whereas the number of patients with statin treatment was significantly larger in the ATT group than the no ATT group. LDL cholesterol levels in the first medical examination were significantly higher in the ATT group than in the no ATT group (149.7 6 44.0 vs 128.7 6 35.5 mg/dL, P , .001). Clinical presentation and angiographic characteristics are shown in Table 2. There was no significant difference in the clinical presentation. The frequency of multivessel
Clinical and angiographic characteristics
Clinical presentation STEMI, n (%) NSTEMI-ACS, n (%) Stable angina, n (%) Angiographic characteristics Multivessel disease, n (%) LM disease, n (%) CTO lesion, n (%)
ATT (1) (N 5 44)
ATT (2) (N 5 197)
6 (13.6) 12 (27.3) 26 (59.1)
56 (28.4) 39 (19.8) 102 (51.8)
35 (79.6) 6 (13.6) 5 (11.4)
115 (58.4) 6 (3.1) 18 (9.1)
P value .113
.009 .004 .650
ACS, acute coronary syndrome; ATT, Achilles tendon thickening; CTO, chronic total occlusion; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; LM, left main. Bold values represent P values with statistical significance (,.05).
Journal of Clinical Lipidology, Vol -, No -, - 2018
4
Figure 2
Forest plot of risk factors for multivessel disease and left main lesion. ATT, Achilles tendon thickening
disease (79.6% vs 58.4%, P 5 .009) and LM lesion (13.6% vs 3.1%, P 5 .004) was significantly higher in the ATT group than in the no ATT group. The frequency of multivessel disease and LM lesion according to subgroups of FH is shown in Supplemental Figure 3. The presence of ATT demonstrated the significant odds of identifying patients with multivessel disease (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.31–6.42, P 5 .007) and LM lesion (OR, 5.03; 95% CI, 1.50–16.9, P 5 .010; Fig. 2, Supplemental Tables 1 and 2). The odds of ATT were the highest among those with hypertension, dyslipidemia, diabetes, chronic kidney disease, and current smoker. Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (Table 3). The ATT group was associated with the presence of intimal vascular channels (50.0% vs 24.7%, P 5 .018), macrophage accumulation (58.3% vs 33.3%, P 5 .028), and a higher tendency of spotty calcification (95.8% vs 80.3%, P 5 .069) compared with the no ATT group (Fig. 3). Quantitative assessment of culprit plaque morphologies is shown in Supplemental Table 3. OCT findings of culprit plaque according to subgroups of FH are shown in Table 4 and Supplemental Figure 4. The definite FH group was associated with the presence of intimal vascular channels and a higher tendency of macrophage accumulation compared with the unlikely FH group.
Discussion The main findings of the present study are as follows: (1) the presence of ATT was significantly associated with multivessel disease and LM disease in patients with CAD requiring PCI; (2) the presence of ATT was independently associated with the presence of multivessel disease; (3) the presence of ATT was associated with the higher incidence of intimal vascular channels and macrophage accumulation in the culprit plaque. Tendon xanthomas are deposits of lipid and connective tissue in tendons and commonly found in patients with FH.1 Several previous studies suggested the similarity between tendon xanthomas and atherosclerotic plaques in terms of
the generating mechanisms and tissue components.15 In an experimental study using 99-m-Technetium-labeled LDL, the origin of accumulated lipids in tendon xanthomas was demonstrated as the circulating LDL rather than local synthesis.16 The circulating LDL is trapped and oxidized in tendon matrix and then taken up from macrophages, resulting in the formation of foam cells15 as it behaves in atherosclerotic plaques. The lipid composition in tendon xanthomas is almost similar to that in atherosclerotic plaques17 with approximately 55% free cholesterol, 28% cholesterol esters, and 13% phospholipids. In addition, other components of atherosclerotic plaques, including calcification, are observed in tendon xanthomas.1 The morphologic responses to pharmacologic therapy in tendon xanthomas are also similar to those in atherosclerotic plaques. Significant regression of ATT was reported in several studies using probucol, statin, and proprotein convertase subtilisin kexin-9 inhibitor.18–21 From these findings, pathophysiological characteristics in tendon xanthomas are considered similar to those in atherosclerotic plaques. In other words, the presence of tendon xanthomas can be a marker for identifying high-risk individuals with advanced and/or vulnerable atherosclerotic plaques. Previous studies have shown the association between tendon xanthomas and the risk of CAD in patients with FH.
Table 3 disease
Independent factor for the presence of multivessel
Variables Model 1 Dyslipidemia, n (%) CKD (eGFR , 60), n (%) ATT, n (%) Model 2 Dyslipidemia, n (%) Diabetes mellitus, n (%) CKD (eGFR , 60), n (%) Family history of IHD, n (%) ATT, n (%)
Odds ratio (95% CI) P value 1.97 (1.10–3.56) 1.91 (1.11–3.31) 2.33 (1.08–5.46)
.022 .020 .031
2.05 1.56 1.98 1.81 2.19
.018 .116 .015 .067 .049
(1.13–3.74) (0.90–2.74) (1.14–3.48) (0.96–3.50) (1.00–5.18)
ATT, Achilles tendon thickening; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IHD, ischemic heart disease. Bold values represent P values with statistical significance (,.05).
Hashimoto et al
Achilles tendon thickening and coronary disease
5
Figure 3 Plaque morphologies of culprit lesion observed using OCT. ATT, Achilles tendon thickening; OCT, optical coherence tomography; TCFA, thin-cap fibroatheroma.
Hirobe et al. reported that Achilles tendon was thicker in FH patients with CAD than in those without CAD.22 A recent meta-analysis demonstrated that tendon xanthomas are associated with a 3.2-fold higher risk of CAD among patients with FH.23 Another recent study reported that a strong positive correlation is observed between Achilles tendon thickness and cholesterol-year scores in patients with FH (r 5 0.86, P , .001).2 In addition to those studies in FH cohort, we demonstrated the association between ATT and the severity of CAD in patients requiring PCI. In the present study, the frequency of multivessel disease and LM lesion was significantly higher in patients with CAD with ATT than those without ATT. This means that ATT might be a marker for detecting individuals with progressed and extended disease among patients with CAD in addition to the role of detecting patients with FH with high CAD risk. In fact, in the present study, the odds of ATT for detecting multivessel disease or LM lesion were higher than those of conventional risk factors. In addition, the presence of ATT was independently associated with the presence of multivessel disease. The present study also demonstrated the association between ATT and vulnerability of culprit plaque. Among plaque components, macrophages have a central role in
Table 4
plaque destabilization by releasing proteolytic enzymes and other proinflammatory mediators that, in turn, can lead to fibrous cap rupture and subsequent thrombotic events.24 Intimal vascular channels are also considered to have an important role for the progression of atherosclerotic plaque. Pathologic studies have reported that intimal vascular channels are more frequently observed in patients with acute myocardial infarction and lesions with TCFA or plaque rupture. OCT studies also demonstrated that intraplaque intimal vascular channels had more TCFAs, thinner fibrous cap, and high-sensitivity C-reactive protein levels, suggesting the importance of intraplaque intimal vascular channels as a marker for plaque vulnerability.11 In addition, Uemura et al. demonstrated that the presence of intimal vascular channels was the potential predictor of subsequent progression of coronary plaque in patients with CAD.25 In the present study, those 2 important components were more frequently observed in the culprit plaque of patients with ATT than in those without ATT. Thus, the presence of ATT might be a marker for identifying high-risk individuals having a vulnerable nature of coronary plaques. The present study has several limitations. First, this was a retrospective study conducted in a single center. Second, we did not perform genetic molecular analysis to diagnose
OCT findings of culprit plaque according to the presence of FH
Lipid plaque, n (%) TCFA (,65 mm), n (%) Macrophage accumulation, n (%) intimal vascular channels, n (%) Calcification, n (%) Thrombus, n (%)
Definite FH (N 5 5)
Probable FH (N 5 20)
Possible FH (N 5 5)
Unlikely FH (N 5 75)
P value
3 2 4 4 4 0
6 3 11 8 20 0
1 0 2 3 5 0
26 15 24 17 67 5
.554 .414 .065 .013 .308 .552
(60.0) (40.0) (80.0) (80.0) (80.0) (0.0)
FH, familial hypercholesterolemia; TCFA, thin-cap fibroatheroma.
(30.0) (15.0) (55.0) (40.0) (100) (0.0)
(20.0) (0.0) (40.0) (60.0) (100.0) (0.0)
(34.7) (20.0) (32.0) (22.7) (89.3) (6.7)
Journal of Clinical Lipidology, Vol -, No -, - 2018
6 genetic FH. ATT at least of mild degree can occur in polygenic hypercholesterolemia and in dysbetalipoproteinemia as well as monogenic FH. The aim of our study was not to diagnose genetic FH but to clarify whether the presence of ATT was associated with disease severity and plaque vulnerability in patients with CAD. Third, ATT can also occur in patients with normolipidemic diseases—for example, tendonitis, trauma, and nodules from rheumatic arthritis or gout. Those cases might not have been excluded from the analysis. Fourth, Achilles tendon thickness was evaluated only by radiography in the present study. Therefore, the prevalence of FH reported in the present study was higher than that evaluated by physical examination in other studies.26 The assessment by other modalities, including magnetic resonance imaging or ultrasonography, may further provide additional diagnostic values.
Conclusions We found that the presence of ATT in patients with CAD was associated with multivessel disease and LM lesion. ATT was also related to intimal vascular channels and macrophage accumulation in the culprit plaque. The presence of ATT might be an indicator for severe CAD and vulnerable coronary plaque.
Acknowledgments None. Conflict of interest: None. Authors’ contributions: T.H. collected and analyzed the data and wrote the article. Y.M. was the corresponding author, conceived the project, and wrote the article. R.K., T.N., and K.F. collected the data. K.M., T.S., and T.T. did the critical revision of the article. J.A. finally approved the article.
Disclosure None.
Supplementary data Supplementary data related to this article can be found online at https://doi.org/10.1016/j.jacl.2018.10.007.
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4. van Aalst-Cohen ES, Jansen AC, Tanck MW, et al. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J. 2006;27:2240–2246. 5. Tada H, Kawashiri MA, Nohara A, et al. Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia. Eur Heart J. 2017;38:1573–1579. 6. Mabuchi H, Ito S, Haba T, et al. Discrimination of familial hypercholesterolemia and secondary hypercholesterolemia by Achilles’ tendon thickness. Atherosclerosis. 1977;28:61–68. 7. Catapano AL, Lautsch D, Tokgozoglu L, et al. Prevalence of potential familial hypercholesteremia (FH) in 54,811 statin-treated patients in clinical practice. Atherosclerosis. 2016;252:1–8. 8. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society. Eur Heart J. 2013;34:3478–3490a. 9. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation. 2005;111:1551–1555. 10. Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International working group for intravascular optical coherence tomography standardization and validation. J Am Coll Cardiol. 2012;59: 1058–1072. 11. Kitabata H, Tanaka A, Kubo T, et al. Relation of microchannel structure identified by optical coherence tomography to plaque vulnerability in patients with coronary artery disease. Am J Cardiol. 2010; 105:1673–1678. 12. Liu L, Gardecki JA, Nadkarni SK, et al. Imaging the subcellular structure of human coronary atherosclerosis using micro-optical coherence tomography. Nat Med. 2011;17:1010–1014. 13. Di Vito L, Yoon JH, Kato K, et al. Comprehensive overview of definitions for optical coherence tomography-based plaque and stent analyses. Coron Artery Dis. 2014;25:172–185. 14. Matsumoto D, Shite J, Shinke T, et al. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J. 2007;28:961–967. 15. Tsouli SG, Kiortsis DN, Argyropoulou MI, et al. Pathogenesis, detection and treatment of Achilles tendon xanthomas. Eur J Clin Invest. 2005;35:236–244. 16. Ginsberg HN, Goldsmith SJ, Vallabhajosula S. Noninvasive imaging of 99mtechnetium-labeled low density lipoprotein uptake by tendon xanthomas in hypercholesterolemic patients. Arteriosclerosis. 1990; 10:256–262. 17. Vermeer BJ, Mateysen AA, van Gent CM, et al. The lipid composition and localization of free and esterified cholesterol in different types of xanthomas. J Invest Dermatol. 1982;78:305–308. 18. Kajinami K, Nishitsuji M, Takeda Y, et al. Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia. Atherosclerosis. 1996;120:181–187. 19. Illingworth DR, Cope R, Bacon SP. Regression of tendon xanthomas in patients with familial hypercholesterolemia treated with lovastatin. South Med J. 1990;83:1053–1057. 20. Lind S, Olsson AG, Eriksson M, et al. Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment. J Intern Med. 2004;256: 406–412. 21. Bea AM, Perez-Calahorra S, Marco-Benedi V, et al. Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia. Atherosclerosis. 2017;263:92–96. 22. Hirobe K, Matsuzawa Y, Ishikawa K, et al. Coronary artery disease in heterozygous familial hypercholesterolemia. Atherosclerosis. 1982;44: 201–210.
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23. Oosterveer DM, Versmissen J, Yazdanpanah M, et al. Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis. 2009;207: 311–317. 24. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143.
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25. Uemura S, Ishigami K, Soeda T, et al. Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques. Eur Heart J. 2012;33:78–85. 26. Faggiano P, Pirillo A, Griffo R, et al. Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: the heredity survey. Int J Cardiol. 2018;252:193–198.
Original Article
Achilles tendon thickening is associated with disease severity and plaque vulnerability in patients with coronary artery disease Takuya Hashimoto, MD, Yoshiyasu Minami, MD, PhD*, Ryota Kakizaki, MD, Teruyoshi Nemoto, MD, Kazuhiro Fujiyoshi, MD, Kentaro Meguro, MD, PhD, Takao Shimohama, MD, PhD, Taiki Tojo, MD, PhD, Junya Ako, MD, PhD Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan (Drs Hashimoto, Kakizaki, Nemoto, Fujiyoshi, and Ako); and Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan (Drs Minami, Meguro, Shimohama, Tojo, and Ako) KEYWORDS: Familial hypercholesterolemia; Optical coherence tomography; Vulnerable plaque; Dyslipidemia; Multivessel disease
BACKGROUND: Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters and a marker of high risk for coronary artery disease (CAD). OBJECTIVE: The aim of the article was to clarify whether the presence of Achilles tendon thickening (ATT) was associated with disease severity and plaque vulnerability in patients with CAD. METHODS: A total of 241 consecutive patients who underwent percutaneous coronary intervention and ATT assessment were analyzed. ATT was defined as Achilles tendon thickness of $9 mm on radiograph. The severity of CAD and plaque vulnerability was assessed by the findings on angiogram and optical coherence tomography, respectively. RESULTS: ATT was found in 44 patients (18.2%). The frequency of multivessel disease (79.6% vs 58.4%, P 5 .009) and left main lesion (13.6% vs 3.1%, P 5 .004) was significantly higher in patients with ATT (ATT group) than in patients without ATT (no ATT group). Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (odds ratio, 2.33; 95% confidence interval, 1.08–5.46; P 5 .031). The ATT group had a higher prevalence of intimal vascular channels (50.0% vs 24.7%, P 5 .018) and macrophage accumulation (58.3% vs 33.3%, P 5 .028) in culprit plaque than the no ATT group. CONCLUSIONS: Patients with the presence of ATT had a higher prevalence of multivessel coronary disease and left main coronary artery disease than with patients without ATT. The presence of ATT was also associated with vulnerable features, including intimal vascular channels and macrophage accumulation in culprit plaques. Ó 2018 National Lipid Association. All rights reserved.
Introduction * Corresponding author. Department of Cardiovascular Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan. E-mail address: [email protected] Submitted May 26, 2018. Accepted for publication October 19, 2018.
1933-2874/Ó 2018 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2018.10.007
Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters.1 Among tendon xanthomas in upper/lower limbs, Achilles tendon xanthomas are the most objective finding because Achilles tendon thickening (ATT) can be quantitatively evaluable on
2 radiography. Although the precise pathophysiology of Achilles tendon xanthomas is still unclear, a recent study reported that a strong positive correlation was observed between Achilles tendon thickness and cholesterol-year score, which is calculated by the age and the mean serum cholesterol concentration of the patients.2 In addition, several previous studies have demonstrated that patients with tendon xanthomas had a higher risk of coronary artery disease (CAD) than those without tendon xanthomas.3,4 Recently, Tada et al. reported that patients with clinical signs of familial hypercholesterolemia (FH; xanthomas and/or family history) or FH gene mutation had 4.6-fold higher odds of developing CAD than those without clinical signs or gene mutation among patients with significantly elevated lowdensity lipoprotein (LDL) cholesterol levels.5 Thus, the presence of ATT may be an indicator of advanced atherosclerosis and/or vulnerable plaque. In the present study, we aimed to clarify whether the presence of ATT was associated with disease severity and plaque vulnerability in patients with CAD.
Methods A total of 296 consecutive patients underwent percutaneous coronary intervention (PCI) at our institution between June 2016 and March 2017. Among them, 241 patients with the measurement of Achilles tendon thickness were enrolled in the present study (Supplemental Fig. 1). Achilles tendon thickness was measured by radiography during hospitalization. The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the ethics committees of our institution. Achilles tendon thickness was measured by soft x-ray radiography according to the recommended method in a guideline (Supplemental Fig. 2).6 In brief, radiograms were taken with each ankle placed lateral side down on the film and the foot flexed at 90 . The anteroposterior diameter of both Achilles tendons was measured at the point of maximal thickening of the tendon except subcutaneous tissue. ATT was defined as the maximum Achilles tendon thickness of $9 mm. The laboratory findings were obtained on admission. Dyslipidemia was defined as LDL cholesterol levels .140 mg/dL and/or use of lipid-lowering drugs. To diagnose FH, baseline LDL cholesterol levels before a prescribed lipid-lowering drugs were additionally collected from hospital record. If baseline values of LDL cholesterol before treatment were not available, we estimated the baseline value with an approximate reduction of LDL cholesterol by 30%.7 A family history of CAD was defined as positive by a first-degree family member having CAD. The diagnosis of FH was based on a modified form of the Dutch Lipid Clinic Network criteria, in which the diagnosis of Achilles tendon xanthoma is based on radiographic criteria rather than physical examination.8 The severity of CAD was assessed by coronary angiography findings. Left main (LM) lesion was defined as a reduction of at least
Journal of Clinical Lipidology, Vol -, No -, - 2018 50% in the luminal diameter of the LM. Multivessel disease was defined as $70% stenosis and/or PCI history in at least one other epicardial coronary artery in addition to culprit artery. Optical coherence tomography (OCT) imaging of culprit lesion was performed in 128 patients. Among them, 105 patients were included in the OCT analysis after excluding 23 patients with poor image quality (n 5 7) or in-stent restenosis (n 5 16). OCT images were acquired using frequency domain OCT (C7-XR Intravascular Imaging System; St Jude Medical, Inc, St Paul, MN) after intracoronary administration of 100 to 200 mg of nitroglycerin. All images were analyzed using offline proprietary software (St Jude Medical). Qualitative and quantitative analyses were performed at 1 mm intervals. All OCT plaque morphologies were assessed according to international consensus standards for intravascular OCT studies.9,10 Fibrous cap thickness was measured at its thinnest part 3 times, and the average value was calculated. Thin-cap fibroatheroma (TCFA) was defined as a lipid plaque with lipid arc .90 and the thickness of fibrous cap ,65 mm. The presence of bright spots within the fibrous cap with backward shadowing was considered indicative of macrophage accumulation.10 Intimal vascular channels were defined as small black holes or tubular structures of 50 to 100 mm diameter that were present within a plaque on at least 3 consecutive cross-sectional frames.10,11 Cholesterol crystals were defined as thin and linear regions of high light intensity without signal attenuation.12 Calcifications were defined as signal-poor or heterogeneous areas delimited by sharp borders. Calcified lesions subtending an arc ,90 and extending in length for 1 to 4 mm were classified as spotty calcium.13 Thrombus was defined as a mass .250 mm attached to the luminal surface or floating within the lumen.10,14 Continuous variables are expressed as mean 6 standard deviation and compared using the unpaired t-test or the Wilcoxon rank-sum test. Categorical variables are presented as numbers and frequencies and compared using the chi-square test. A univariate logistic regression model was used to assess the predictor of multivessel disease and LM trunk lesion. Multivariate logistic regression models were further used to assess the predictor of
Figure 1
Distribution of Achilles tendon thickness.
Hashimoto et al Table 1
Achilles tendon thickening and coronary disease
3
Baseline characteristics
Demographic characteristics Age, y Male gender, n (%) BMI Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Current smoker, n (%) Chronic kidney disease, n (%) Family history of CAD, n (%) Previous MI, n (%) Previous PCI, n (%) Previous CABG, n (%) Laboratory findings LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL Hemoglobin A1c, % eGFR, mL/min/1.73 m2 BNP, pg/mL Medications Statin, n (%) Ezetimibe, n (%)
ATT (1) (N 5 44)
ATT (2) (N 5 197)
P value
66.0 6 10.4 40 (90.9) 24.6 6 3.2 36 (81.8) 36 (81.8) 22 (50.0) 7 (15.9) 29 (65.9) 15 (34.1) 16 (36.4) 21 (47.7) 2 (4.6)
69.3 6 10.7 152 (77.2) 24.1 6 3.5 150 (76.1) 134 (68.0) 83 (42.1) 47 (23.9) 96 (48.7) 50 (25.4) 54 (27.4) 59 (30.0) 4 (2.0)
.068 .040 .424 .417 .070 .341 0.253 .039 .239 .237 .024 .333
99.7 6 33.7 47.6 6 12.4 177.1 6 118.5 6.4 6 1.7 49.7 6 24.5 87.3 (38.3–166.5)
104.6 6 38.3 50.9 6 13.9 150.4 6 104.9 6.5 6 0.1 59.1 6 20.1 72.3 (29.2–188.0)
.447 .149 .141 .614 .007 .742
36 (81.8) 6 (13.6)
117 (59.4) 11 (5.6)
.005 .059
ATT, Achilles tendon thickening; BMI, body mass index; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention. Bold values represent P values with statistical significance (,.05).
multivessel disease. We included the factors with P , .05 and those with P , .10 in univariate logistic regression model into the model 1 and model 2, respectively. A P value , .05 was used to indicate statistical significance. All analyses were performed using JMP version 12.0.1 for Windows (SAS, NC).
Results Mean Achilles tendon thickness was 7.9 6 1.6 mm. ATT was found in 44 patients (18.2%; Fig. 1). Baseline characteristics according to the presence of ATT are shown in Table 2
Table 1. The prevalence of males was higher in the ATT group than in the no ATT group. ATT was associated with higher prevalence of chronic kidney disease and history of PCI. There were no significant differences in LDL cholesterol levels between the 2 groups, whereas the number of patients with statin treatment was significantly larger in the ATT group than the no ATT group. LDL cholesterol levels in the first medical examination were significantly higher in the ATT group than in the no ATT group (149.7 6 44.0 vs 128.7 6 35.5 mg/dL, P , .001). Clinical presentation and angiographic characteristics are shown in Table 2. There was no significant difference in the clinical presentation. The frequency of multivessel
Clinical and angiographic characteristics
Clinical presentation STEMI, n (%) NSTEMI-ACS, n (%) Stable angina, n (%) Angiographic characteristics Multivessel disease, n (%) LM disease, n (%) CTO lesion, n (%)
ATT (1) (N 5 44)
ATT (2) (N 5 197)
6 (13.6) 12 (27.3) 26 (59.1)
56 (28.4) 39 (19.8) 102 (51.8)
35 (79.6) 6 (13.6) 5 (11.4)
115 (58.4) 6 (3.1) 18 (9.1)
P value .113
.009 .004 .650
ACS, acute coronary syndrome; ATT, Achilles tendon thickening; CTO, chronic total occlusion; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; LM, left main. Bold values represent P values with statistical significance (,.05).
Journal of Clinical Lipidology, Vol -, No -, - 2018
4
Figure 2
Forest plot of risk factors for multivessel disease and left main lesion. ATT, Achilles tendon thickening
disease (79.6% vs 58.4%, P 5 .009) and LM lesion (13.6% vs 3.1%, P 5 .004) was significantly higher in the ATT group than in the no ATT group. The frequency of multivessel disease and LM lesion according to subgroups of FH is shown in Supplemental Figure 3. The presence of ATT demonstrated the significant odds of identifying patients with multivessel disease (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.31–6.42, P 5 .007) and LM lesion (OR, 5.03; 95% CI, 1.50–16.9, P 5 .010; Fig. 2, Supplemental Tables 1 and 2). The odds of ATT were the highest among those with hypertension, dyslipidemia, diabetes, chronic kidney disease, and current smoker. Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (Table 3). The ATT group was associated with the presence of intimal vascular channels (50.0% vs 24.7%, P 5 .018), macrophage accumulation (58.3% vs 33.3%, P 5 .028), and a higher tendency of spotty calcification (95.8% vs 80.3%, P 5 .069) compared with the no ATT group (Fig. 3). Quantitative assessment of culprit plaque morphologies is shown in Supplemental Table 3. OCT findings of culprit plaque according to subgroups of FH are shown in Table 4 and Supplemental Figure 4. The definite FH group was associated with the presence of intimal vascular channels and a higher tendency of macrophage accumulation compared with the unlikely FH group.
Discussion The main findings of the present study are as follows: (1) the presence of ATT was significantly associated with multivessel disease and LM disease in patients with CAD requiring PCI; (2) the presence of ATT was independently associated with the presence of multivessel disease; (3) the presence of ATT was associated with the higher incidence of intimal vascular channels and macrophage accumulation in the culprit plaque. Tendon xanthomas are deposits of lipid and connective tissue in tendons and commonly found in patients with FH.1 Several previous studies suggested the similarity between tendon xanthomas and atherosclerotic plaques in terms of
the generating mechanisms and tissue components.15 In an experimental study using 99-m-Technetium-labeled LDL, the origin of accumulated lipids in tendon xanthomas was demonstrated as the circulating LDL rather than local synthesis.16 The circulating LDL is trapped and oxidized in tendon matrix and then taken up from macrophages, resulting in the formation of foam cells15 as it behaves in atherosclerotic plaques. The lipid composition in tendon xanthomas is almost similar to that in atherosclerotic plaques17 with approximately 55% free cholesterol, 28% cholesterol esters, and 13% phospholipids. In addition, other components of atherosclerotic plaques, including calcification, are observed in tendon xanthomas.1 The morphologic responses to pharmacologic therapy in tendon xanthomas are also similar to those in atherosclerotic plaques. Significant regression of ATT was reported in several studies using probucol, statin, and proprotein convertase subtilisin kexin-9 inhibitor.18–21 From these findings, pathophysiological characteristics in tendon xanthomas are considered similar to those in atherosclerotic plaques. In other words, the presence of tendon xanthomas can be a marker for identifying high-risk individuals with advanced and/or vulnerable atherosclerotic plaques. Previous studies have shown the association between tendon xanthomas and the risk of CAD in patients with FH.
Table 3 disease
Independent factor for the presence of multivessel
Variables Model 1 Dyslipidemia, n (%) CKD (eGFR , 60), n (%) ATT, n (%) Model 2 Dyslipidemia, n (%) Diabetes mellitus, n (%) CKD (eGFR , 60), n (%) Family history of IHD, n (%) ATT, n (%)
Odds ratio (95% CI) P value 1.97 (1.10–3.56) 1.91 (1.11–3.31) 2.33 (1.08–5.46)
.022 .020 .031
2.05 1.56 1.98 1.81 2.19
.018 .116 .015 .067 .049
(1.13–3.74) (0.90–2.74) (1.14–3.48) (0.96–3.50) (1.00–5.18)
ATT, Achilles tendon thickening; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IHD, ischemic heart disease. Bold values represent P values with statistical significance (,.05).
Hashimoto et al
Achilles tendon thickening and coronary disease
5
Figure 3 Plaque morphologies of culprit lesion observed using OCT. ATT, Achilles tendon thickening; OCT, optical coherence tomography; TCFA, thin-cap fibroatheroma.
Hirobe et al. reported that Achilles tendon was thicker in FH patients with CAD than in those without CAD.22 A recent meta-analysis demonstrated that tendon xanthomas are associated with a 3.2-fold higher risk of CAD among patients with FH.23 Another recent study reported that a strong positive correlation is observed between Achilles tendon thickness and cholesterol-year scores in patients with FH (r 5 0.86, P , .001).2 In addition to those studies in FH cohort, we demonstrated the association between ATT and the severity of CAD in patients requiring PCI. In the present study, the frequency of multivessel disease and LM lesion was significantly higher in patients with CAD with ATT than those without ATT. This means that ATT might be a marker for detecting individuals with progressed and extended disease among patients with CAD in addition to the role of detecting patients with FH with high CAD risk. In fact, in the present study, the odds of ATT for detecting multivessel disease or LM lesion were higher than those of conventional risk factors. In addition, the presence of ATT was independently associated with the presence of multivessel disease. The present study also demonstrated the association between ATT and vulnerability of culprit plaque. Among plaque components, macrophages have a central role in
Table 4
plaque destabilization by releasing proteolytic enzymes and other proinflammatory mediators that, in turn, can lead to fibrous cap rupture and subsequent thrombotic events.24 Intimal vascular channels are also considered to have an important role for the progression of atherosclerotic plaque. Pathologic studies have reported that intimal vascular channels are more frequently observed in patients with acute myocardial infarction and lesions with TCFA or plaque rupture. OCT studies also demonstrated that intraplaque intimal vascular channels had more TCFAs, thinner fibrous cap, and high-sensitivity C-reactive protein levels, suggesting the importance of intraplaque intimal vascular channels as a marker for plaque vulnerability.11 In addition, Uemura et al. demonstrated that the presence of intimal vascular channels was the potential predictor of subsequent progression of coronary plaque in patients with CAD.25 In the present study, those 2 important components were more frequently observed in the culprit plaque of patients with ATT than in those without ATT. Thus, the presence of ATT might be a marker for identifying high-risk individuals having a vulnerable nature of coronary plaques. The present study has several limitations. First, this was a retrospective study conducted in a single center. Second, we did not perform genetic molecular analysis to diagnose
OCT findings of culprit plaque according to the presence of FH
Lipid plaque, n (%) TCFA (,65 mm), n (%) Macrophage accumulation, n (%) intimal vascular channels, n (%) Calcification, n (%) Thrombus, n (%)
Definite FH (N 5 5)
Probable FH (N 5 20)
Possible FH (N 5 5)
Unlikely FH (N 5 75)
P value
3 2 4 4 4 0
6 3 11 8 20 0
1 0 2 3 5 0
26 15 24 17 67 5
.554 .414 .065 .013 .308 .552
(60.0) (40.0) (80.0) (80.0) (80.0) (0.0)
FH, familial hypercholesterolemia; TCFA, thin-cap fibroatheroma.
(30.0) (15.0) (55.0) (40.0) (100) (0.0)
(20.0) (0.0) (40.0) (60.0) (100.0) (0.0)
(34.7) (20.0) (32.0) (22.7) (89.3) (6.7)
Journal of Clinical Lipidology, Vol -, No -, - 2018
6 genetic FH. ATT at least of mild degree can occur in polygenic hypercholesterolemia and in dysbetalipoproteinemia as well as monogenic FH. The aim of our study was not to diagnose genetic FH but to clarify whether the presence of ATT was associated with disease severity and plaque vulnerability in patients with CAD. Third, ATT can also occur in patients with normolipidemic diseases—for example, tendonitis, trauma, and nodules from rheumatic arthritis or gout. Those cases might not have been excluded from the analysis. Fourth, Achilles tendon thickness was evaluated only by radiography in the present study. Therefore, the prevalence of FH reported in the present study was higher than that evaluated by physical examination in other studies.26 The assessment by other modalities, including magnetic resonance imaging or ultrasonography, may further provide additional diagnostic values.
Conclusions We found that the presence of ATT in patients with CAD was associated with multivessel disease and LM lesion. ATT was also related to intimal vascular channels and macrophage accumulation in the culprit plaque. The presence of ATT might be an indicator for severe CAD and vulnerable coronary plaque.
Acknowledgments None. Conflict of interest: None. Authors’ contributions: T.H. collected and analyzed the data and wrote the article. Y.M. was the corresponding author, conceived the project, and wrote the article. R.K., T.N., and K.F. collected the data. K.M., T.S., and T.T. did the critical revision of the article. J.A. finally approved the article.
Disclosure None.
Supplementary data Supplementary data related to this article can be found online at https://doi.org/10.1016/j.jacl.2018.10.007.
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