The Role of the Vascular and Structural Response to Activity in the Development of Achilles Tendinopathy: A Prospective Study

Abstract

Background:

Several risk factors have been suggested in the development of Achilles tendinopathy, but large-scale prospective studies are limited.

Purpose:

To investigate the role of the vascular response to activity of the Achilles tendon, tendon thickness, ultrasound tissue characterization (UTC) of tendon structure, and foot posture as possible risk factors in the development of Achilles tendinopathy.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

The study began with 351 first-year students at Ghent University. After 51 students were excluded, 300 were tested in the academic years 2013-2014 and 2014-2015 and were followed prospectively for 2 consecutive years by use of a multilevel registration method. Of those, 250 students were included in the statistical analysis. At baseline, foot posture index and UTC were investigated bilaterally. Blood flow and tendon thickness were measured before and after a running activity. Cox regression analyses were performed to identify significant contributors to the development of Achilles tendinopathy.

Results:

During the 2-year follow-up, 27 of the included 250 participants developed Achilles tendinopathy (11%). Significant predictive effects were found for female sex and blood flow response after running (P = .022 and P = .019, respectively). The risk of developing Achilles tendinopathy increased if the blood flow increase after running was reduced, regardless of sex, foot pronation, and timing of flow measurements. The model had a predictive accuracy of 81.5% regarding the development of Achilles tendinopathy, with a specificity of 85.0% and a sensitivity of 50.0%.

Conclusion:

This prospective study identified both female sex and the diminished blood flow response after running as significant risk factors for the development of Achilles tendinopathy. UTC of tendon structure, Achilles tendon thickness, and foot posture did not significantly contribute to the prediction of Achilles tendinopathy. A general evaluation of tendon structure by UTC, measurement of tendon thickness, or determination of the foot posture index will not allow clinicians to identify patients at risk for developing Achilles tendinopathy. Furthermore, it may be possible to improve blood flow after activity by using noninvasive techniques (such as prostaglandins, compression stockings, heat, massage, and vibration techniques). These techniques may be useful in the prevention and management of Achilles tendinopathy, but further research is needed.

Keywords

prospective study risk factors Achilles tendinopathy blood flow thickness foot posture ultrasound tissue characterization (UTC)running

Although the Achilles tendon is the largest and strongest tendon in the human body, injuries are common.⁴¹ The most common Achilles tendon injury is tendinopathy.² Despite the high prevalence and the often deleterious consequences of Achilles tendinopathy (AT), many aspects of its origin remain unknown.

Several risk factors for AT have been suggested, but large-scale prospective studies are lacking.^7,13,29,45 Although both structural and vascular factors have been suggested as risk factors for the development of AT, it remains unclear whether these structural or vascular parameters predict future symptoms. Previous studies reported the need for longitudinal studies to investigate the physiological or pathological effect of vascularization after activity and its predictive value in the development of AT.^6,33 Furthermore, the identification of Achilles tendon abnormalities, visualized by ultrasound imaging, showed conflicting results as a risk factor for the development of AT, since these structural abnormalities could be caused by load and are also present in a large percentage of asymptomatic sporting populations.^8,16,21,28 A relatively new technique was developed to optimize the visualization of tendon structure.⁴⁸ This novel technique, ultrasound tissue characterization (UTC), has been demonstrated to be suitable to quantify subtle changes in tendon structure.^{10-12,44,48,51} Despite increasing publications on the use of UTC, no prospective studies have been published to date.

The lack of clarity on specific risk factors has led to considerable uncertainty in the management and prevention of AT. Therefore, the aim of this prospective study was to investigate the role of the Achilles tendon thickness, vascular response to activity, foot posture, and UTC tendon structure as possible risk factors in the development of AT.

Methods

Study Design

In this prospective cohort study, at the start of the 2013-2014 and 2014-2015 academic years, blood flow, Achilles tendon thickness, UTC, and Foot Posture Index (FPI) evaluations of both Achilles tendons were performed in randomized order in all subjects. Then, participants were instructed to perform a physical activity, and thereafter the blood flow measurements and ultrasound examination were repeated. Participants were instructed not to engage in any sports activities 48 hours before testing to ensure a valid resting state measure. The subjects also completed a questionnaire concerning demographic and anthropometric data, sport activities, and injury history. After these measurements, injury registration was performed during a follow-up period of 2 consecutive years or until the end of the academic year 2015-2016. For 29 weeks per academic year, the participants followed the same sports program under similar environmental conditions as part of their education. The average weekly sports participation (sum of basic sports education, practice hours, and sports participation outside the official educational program) was registered, and this total amount of sports participation was individually used as time at risk for every subject. The time at risk was registered from the start of the study until the injury, or until the end of the study for students who did not develop an injury. In case of dropout, the time until last personal contact was taken into account for the individual time at risk. This study was approved by the Ethics Committee of the Ghent University Hospital (approval No. EC/2013/616).

Participants

This study began with 351 freshmen students at Ghent University. Participants were excluded from the study if they had a history of AT, surgery of the lower extremity, or severe trauma in the lower extremity within the previous year. This resulted in 300 included participants (141 male and 159 female), with a mean age of 18.0 ± 0.8 years (Table 1). All students were evaluated in the academic years 2013-2014 and 2014-2015. Of those, 250 were included in statistical analysis, since 50 students developed other lower extremity injuries (no AT) and were therefore excluded from analysis. Of the 250 participants, 27 developed AT; 223 participants did not sustain any injury of the lower extremity and were used as control subjects (Figure 1).

Table 1

Subject Characteristics and Tendon Characteristics for the Control Group and Achilles Tendinopathy (AT) Group

Characteristics and Tendon Characteristics^a	Control Group (n = 223)^b	AT Group (n = 27)^b	P Value^c
Age, y	18.03 ± 0.87	17.85 ± 0.53	.374
Height, m	1.75 ± 0.08	1.72 ± 0.08	.028
Weight, kg	64.43 ± 9.05	61.03 ± 7.01	.015
Body mass index, kg/m²	21.08 ± 2.04	20.52 ± 1.68	.166
Rating of perceived exertion	5.6 ± 1.8	5.2 ± 1.4	.465
Sport participation, h/wk	6.85 ± 4.90	8.64 ± 5.23	.256
Midportion echo type I, % [6]	55.82 ± 15.17	55.48 ± 14.71	.394
Midportion echo type II, % [6]	40.47 ± 12.21	40.49 ± 11.93	.297
Midportion echo type III, % [6]	3.19 ± 5.85	3.47 ± 3.92	.865
Midportion echo type IV, % [6]	0.53 ± 0.92	0.56 ± 0.67	.655
Flow midportion, pre, arbitrary units [3]	48.98 ± 19.33	47.87 ± 19.58	.351
Flow midportion, post, arbitrary units [3]	77.57 ± 34.46	66.71 ± 25.89	.065
Flow midportion increase, arbitrary units [3]	28.71 ± 27.09	19.05 ± 23.19	.146
Thickness 2 cm proximal to calcaneal border, pre, mm [1]	4.44 ± 0.61	4.21 ± 0.67	.026
Thickness 5 cm proximal to calcaneal border, pre, mm [2]	3.61 ± 0.73	3.48 ± 0.68	.548
Thickness 2 cm proximal to calcaneal border, post, mm [1]	4.34 ± 0.62	4.12 ± 0.62	.056
Thickness 5 cm proximal to calcaneal border, post, mm [2]	3.61 ± 0.78	3.60 ± 0.79	.981
Sex, n (%)			.013
Male	104/223 (47)	9/27 (33)
Female	119/223 (53)	18/27 (67)
Dominance, n (%)			.805
Dominant leg	74/223 (33)	9/27 (33)
Nondominant leg	149/223 (67)	18/27 (67)
Foot posture [3], n (%)			.594
Pronated foot	41/221 (19)	4/26 (15)
Neutral or supinated foot	180/221 (81)	22/26 (85)

Brackets indicate numbers of missing values. Pre and post refer to before and after the running activity.

Data expressed as mean ± SD or n (%).

P values were obtained by univariate Cox regression analyses.

Blood Flow Measurement

Blood flow data at the midportion of the Achilles tendon were collected by use of the oxygen-to-see (O2C) device (LEA Medizintechnik). This noninvasive device is capable of measuring the perfusion and oxygenation of the subcutaneous tissue using an optical flat fiber probe. Measurements were performed as described by Wezenbeek et al⁵² at a depth of 8 mm. The head of the probe was placed flat on the tissue at the measurement point, without pressure or movement. For standardization purposes, measurements were performed in a darkened room with constant temperature. The stability of the blood flow measurements has been investigated, and the measurement has been shown to be reliable and valid.^15,52 A 2-way, mixed, single-measures intraclass correlation (ICC) for absolute agreement as a measure for intraobserver reliability was 0.75 and minimal detectable change was calculated as 9.2 arbitrary units (AU).

Achilles Tendon Thickness

Bilateral gray-scale ultrasonographic examinations of the thickness of the Achilles tendons were performed by use of a high-resolution, linear array, 11.4-MHz ultrasound transducer (Siemens Acuson X150 [Siemens NV] and Logic Scan 128 [Telemed]). Participants were placed in prone position with both feet hanging freely off the examination table. The tendon thickness was assessed in the transverse plane, and the true tendon thickness was measured at distances of 2 and 5 cm proximal to the calcaneal border. The reliability of the thickness measurements was investigated in 10 Achilles tendons of age-matched subjects on 2 different measurement days in the same week. The ICC was 0.78 and 0.83 at 2 and 5 cm, respectively, and minimal detectable changes were calculated as 0.4 mm for both 2 and 5 cm.

Ultrasound Tissue Characterization

Tissue characterization was performed in all participants. The protocol for this measurement was described in detail by Wezenbeek et al.⁵¹ For analysis, the midportion volume 2 to 6 cm proximal of the calcaneus, starting from the proximal border of the calcaneus, was used. Images were analyzed by selecting a region of interest (ROI), defined by the outline of the Achilles tendon in the transverse plane. Nine ROIs were placed in the longitudinal plane at regular intervals of 5 mm. Contours were then interpolated between these contiguous ROIs, creating a tendon volume of the midportion (2-6 cm), in which the proportions of echo types were quantified. Four valid echo types can be discriminated: echo type I represents intact, continuous, and aligned fibers and fasciculi; echo type II represents less continuous and/or more wavy fibers and fasciculi; echo type III represents a mainly fibrillar matrix; and echo type IV represents complete disintegration, with tendon tissue replaced by an amorphous matrix and fluid.⁴⁸ The window size used for interpolation was 17; that is, the tendon structure was quantified with dedicated UTC algorithms that assessed the echo pattern by means of relative intensity and distribution of gray levels of corresponding pixels over 17 images (3.2 mm). Test-retest reliability was investigated; ICCs for intraobserver reliability were between 0.96 and 0.98, and minimal detectable changes were calculated as 7.0%, 6.5%, 0.8%, and 0.2% for the 4 echo types, respectively.⁵¹

Foot Posture Index

Foot posture was quantified by use of the FPI, a 6-item foot posture assessment tool. The assessment was conducted as described by Redmond et al.⁴² High positive aggregate values (values between +6 and +12) indicate a pronated posture, whereas more neutral (0 to +5) and negative values (–1 to –12) indicate, respectively, more neutral or supinated foot posture.⁴² The assessment tool has been shown to be reliable and valid.^30,42

Physical Activity

Participants were instructed to run 1.92 km at an average running pace of 3.2 m/s. Participants ran shod on a Finnish track, wearing self-selected running shoes.

Injury Registration and Diagnostic Criteria

Since the injury registration method and diagnostic criteria are very important in injury recording,³ a multilevel registration method and accurate diagnostic criteria were used. A primary online registration method was used to identify students with Achilles tendon pain or dysfunction. For this online method, the participants received a weekly reminder by email to register their injuries in an online questionnaire. When subjects had an Achilles tendon complaint, further diagnosis of the AT was performed by an experienced physician. More specifically, 1 or more of the following criteria were used for diagnosing AT: (1) an atraumatic occurrence of noninsertional Achilles tendon pain, exacerbated by running; (2) the presence of swelling at the midportion of the Achilles tendon; (3) noninsertional pain, ache, or soreness of the Achilles tendon with possible functional limitation during physical activity.^25,47 Every 3 months, participant interviews were conducted to check compliance with the injury registration and, if needed, to confirm the occurrence of AT.

Statistical Analysis

The injured leg of the participants who developed AT was used in the statistical analysis. If a participant developed bilateral symptoms, only the more painful tendon was included, based on a visual analog scale score. The injured legs were matched with legs of the control group such that the percentage of dominant legs in the control group matched the percentage of dominant legs in the injured group. Therefore, 1 leg per participant of the control group was randomly selected until the ratio of nondominant to dominant legs of the control group was equal to that of the injured group (Figure 1).

Statistical analysis was conducted with the SPSS V.23 statistical software (IBM Corp). First, univariate Cox regression analyses were performed allowing reduction of the number of variables since variables were included for further analysis only if P < .2. Second, stepwise multivariate Cox regression analyses were performed to identify significant contributors to the development of AT while correlations were checked between covariates to exclude multicollinearity. Variables with a P < .05 in the Cox regression analysis were seen as significant predictors for AT.

Results

During the follow-up period, 27 of the 250 included participants developed AT (11%). A total of 223 of the 250 participants did not sustain any injuries of the lower leg and served as the control group (89%). The AT injury rate was 0.3 events per 1000 hours of sports participation. Subject characteristics, tendon characteristics, and results of the univariate Cox regression are reported in Table 1.

Cox Regression

In the model building, correlations were seen between height, weight, body mass index, tendon thickness, and sex and also between blood flow after activity and the increase in blood flow after activity. After stepwise, multivariate, Cox proportional hazards model building for the development of AT, the final model included the variables sex, increase in blood flow after running, timing of blood flow measurements, and foot posture. The timing of blood flow measurements and foot posture were included as confounders in the analyses since previous studies showed that the Achilles tendon blood flow after activity had a fast increase followed by a quick recovery to baseline⁴³ and since recent studies confirmed the relationship between foot pronation and Achilles tendon blood flow.^22,52 The results of the multivariate Cox regression analysis and the strength of the predictive values are presented in Table 2.

Table 2

Risk Model for the Prediction of Achilles Tendinopathy Versus No Injury Obtained by Multivariate Cox Regression

Indicator	β	SE	P Value^a	Hazard Ratio	95% Confidence Interval
Increase in blood flow	−0.026	0.011	.019	0.974	0.953-0.996
Pronation	−0.285	0.552	.605	0.752	0.255-2.217
Instantly measured	0.552	0.594	.353	1.736	0.542-5.562
Female sex	1.038	0.454	.022	2.822	1.160-6.866

Boldface indicates statistical significance.

The multivariate Cox regression analysis showed a significant predictive effect of female sex and increase of blood flow after running. The hazard of developing AT increased by 3% if the blood flow increase after running was lowered by 1 AU, regardless of sex, foot pronation, and timing of flow measurements. Based on the current model, prognostic scores were calculated and a cut-off value of 0.73 was determined to indicate a group with high prognostic score and a group with low prognostic score. The model had a predictive accuracy of 81.5% regarding the development of AT, with a specificity of 85.0% and a sensitivity of 50.0%. The Kaplan-Meier survival curve of the high- and low-risk groups is displayed in Figure 2.

Discussion

The results of this study identified both female sex and the blood flow response after running as risk factors for the development of AT. Interestingly, in this study no association was found between AT and Achilles tendon thickness, UTC, or pronated foot posture.

Vascular Parameters and Injury Risk

Physical activity generates an increased metabolic demand. To fulfill this increased metabolic demand, a cardiovascular redistribution of blood flow to the working soft tissues is induced.¹⁴ Consequently, an increase in Achilles tendon blood flow as a normal physiological response to activity has been observed.³⁷

This study is the first to investigate the amount of blood flow increase after running as a risk factor for the development of AT. The results of this study showed that the lower the increase in blood flow after running, the higher the hazard for developing AT. The difference in increase in blood flow between the AT and control group was greater than the minimal detectable change. Our results are in line with previous research showing that a decrease of the tendon blood supply results in hypoxia, which has been demonstrated to regulate inflammatory and apoptotic factors in tendon cells and to promote a “switch” in collagen matrix synthesis.²⁶ This resultant altering of material properties leads to weakening of the normal tendon structure.³⁹ In addition, it is suggested that in a hypovascular structure, the extent of necessary matrix remodeling is restricted.⁴⁰ A further suggestion is that an insufficient blood supply could indicate anaerobic conditions in the tendon. This suggestion is supported by previous studies that found significantly higher lactate levels in pathological Achilles tendons compared with normal tendons.¹ Pufe et al³⁹ stated that the recovery process takes longer in hypovascular tissue and there is a higher chance that a damaging force is reapplied before this recovery occurs. Therefore, it is not very surprising that a lower increase in blood flow after running is associated with AT. Indeed, it is plausible that a lower increase in blood flow after running creates insufficient or delayed regeneration of the tendon due to insufficient recovery between training loads, explaining the higher hazard for developing AT. Although previous research reported no significant difference in blood flow values before and after activity between this population and an older population,²⁴ and it can therefore be assumed that this risk factor is not age-dependent, further study is indicated to verify this assumption.

Given that we have identified an association between a lower increase in blood flow after running and the development of AT, it seems logical that the increase in blood flow after activity should be stimulated. It is possible that the participants with a lower increase in blood flow after running need a longer warm-up to improve the vascular response to activity. It has been reported that warming up before a sport event enhances performance and decreases injury risk since an induced increase in body temperature leads to vasodilation of the blood vessels in the working soft tissues, subsequently leading to an increase in blood flow.²⁰ Furthermore, prostaglandins are indicated to elevate blood flow during increased metabolic demands such as exercise.⁵ Compression stockings, heat, massage, and vibration techniques are suggested to increase the blood flow and therefore might facilitate recovery after activity^{17,23,38,49,50}; however, further research is needed to investigate the vascular response of these techniques in the Achilles tendon since current literature is limited to changes in blood flow at the skin surface. Because the current study identified that the hazard for developing AT is higher when the increase in blood flow after running is lowered, further investigation is needed regarding the factors that influence this vascular response, such as smoking, body mass index, diabetes, tendon structure, high cholesterol levels, genetics, nutrition, and age. Prior research showed that more eversion excursion during running led to a significant decrease in Achilles tendon blood flow after running, and measures that decrease pronation during running are suggested to be useful in both preventing and managing AT.⁵² However, further research is needed to ensure that reducing eversion excursion increases blood flow.

Sex and Injury Risk

This was the first study to investigate sex as a risk factor for the development of AT. Although sex is often mentioned as a risk factor for AT (particularly men are suggested to be at higher risk), it is remarkable that this has never been studied prospectively. The results of this study found an association between female sex and an increased hazard for the development of AT. It is possible that sex differences in AT incidence may simply be the result of sex-related differences in reporting injuries or seeking care.³⁴ Also, it could be that women in our study were less resistant to the increased load of the sports program compared with their male counterparts, since no adjustment in physical activity was made for sex in the educational program. Magnan et al²⁶ suggested that the higher incidence of AT reported in males may not reflect higher susceptibility of males to AT, since differences in physical activity make it difficult to evaluate sex as an independent etiological factor. Therefore, it is plausible that in a young adult population, females are at higher risk of developing AT versus males when performing a program with similar load. This finding should be considered when a similar physical activity load is imposed on males and females, such as in the military or in educational programs.

Structural Parameters and Injury Risk

Interestingly, this study did not identify structural parameters, such as the Achilles tendon thickness and tendon structure as defined by UTC, as predictive parameters for the development of AT. Despite increasing publications on the use of UTC, it is striking that to date, the present study is the first to prospectively investigate the role of tendon structure, defined by UTC, in the development of AT. In this study, the amount of echo type II could not be identified as a risk factor for the development of AT in active, healthy young adults. This is not surprising since echo type II tendon bundles are not pathological and can be considered as a normal physiological finding in an active, young adult population.⁵¹ In contrast, prior research identified the presence of echo types III and IV as indicating inferior tendon quality and potentially a pathological tendon.⁴⁸ In our study, the presence of echo types III and IV was marginal (3.88% ± 6.63% and 0.77% ± 1.38%, respectively). As a consequence, the results of this study do not allow a conclusion concerning the increased risk of AT based on the presence of echo types III and IV. It is possible that evaluation of the entire midportion volume is not suitable to quantify subtle differences in tendon structure that may precede the development of symptoms. Furthermore, previous research stated that UTC tendon structure differs between sexes, and different locations in the tendon should be taken into account.⁵¹

Next, our results were not able to identify the Achilles tendon thickness as a possible risk factor for the development of AT. The reported tendon thickness in this study was in accordance with previous studies^8,18; however, comparison with previous literature is difficult since ultrasound materials and measurement techniques vary between studies. Several longitudinal studies have investigated whether tendon thickness in asymptomatic individuals is predictive for future symptomatic tendinopathy, with conflicting results. The results of this study are in agreement with those of Comin et al,⁸ who investigated tendon thickness in 79 professional ballet dancers and found no correlation between thickness and the development of symptoms. Giombini et al¹⁸ and Hirschmuller et al¹⁹ examined Achilles tendons in 37 elite fencers and 634 runners, respectively, and found that Achilles tendon thickness could not predict the development of symptoms. In contrast, 2 studies found that soccer or football players with thicker Achilles tendons were more at risk to develop symptoms: namely, Ooi et al,³⁶ who tested 42 elite Australian football players with a mean age of 24 years (range, 18-34 years), and Jhingan et al,²¹ who tested 18 elite soccer players with a mean age of 23.5 years (range, 22-27.5 years). The conflicting result with these 2 studies might possibly be explained by our study population. It is possible that our results did not identify tendon thickness as a risk factor in this active, young adult population since participants with a history of Achilles tendon complaints were excluded from this study (in contrast to the population tested by Jhingan et al). This indicates that AT diagnosed in our study is probably initial tendon disease and not advanced tendon disease; increased tendon thickness is more frequently associated with tendon degeneration, and this stage is primarily seen in older people or in people with previous complaints.^9,27 As well, in this study we measured true tendon thickness at fixed distances from the calcaneal border. This is in contrast to the study by Ooi et al, who identified the maximum tendon thickness as a risk factor for the development of AT. Since we did not register the maximum tendon thickness, no conclusion regarding this possible risk factor could be drawn in our study.

Foot Posture and Injury Risk

In this study, a pronated foot as defined by the FPI was not associated with an increased hazard for the development of AT. Previous studies identified the pronated foot posture as defined by the FPI as a risk factor for various lower limb injuries, such as medial tibial stress syndrome, patellofemoral pain syndrome, and ankle sprains, but no relationship was identified between FPI and AT.^32,35 However, it has been suggested that excessive foot pronation creates a whipping or torsional action on the Achilles tendon, which causes vascular blanching of the midportion of the Achilles tendon as the foot rotates rapidly from an inverted position at heel strike to an excessively everted position in midstance.⁷ This whipping hypothesis is supported by some retrospective studies demonstrating greater rearfoot eversion and greater rearfoot eversion range of motion during running than in controls.^13,29,45 Recent studies confirmed this relationship between foot pronation and Achilles tendon blood flow.^22,52 Indeed, Wezenbeek et al⁵² showed that the more eversion excursion that was observed, the lower the increase in blood flow after running. Therefore, it is surprising that foot pronation, defined by the FPI, could not be associated with an increased risk for the development of AT. A possible explanation is that the FPI, assessed in static position, was not sensitive enough as a predictor of eversion range of motion during a dynamic running activity. Furthermore, although the FPI has been shown to be a reliable and valid assessment tool by several authors,^30,42 some authors state that caution is needed when interpreting the FPI results,⁴⁶ more specifically when participants are categorized into a certain foot type based on their FPI score, since this may limit the sensitivity of the index.⁴ Also, the FPI in the current study was evaluated in barefoot condition, whereas pronation of the foot is increased in running shoes.³¹

Methodological Considerations

This is the first large-scale prospective study to investigate the role of the Achilles tendon thickness and vascular response to activity, foot posture, and UTC tendon structure as possible risk factors in the development of AT. This was studied in an active, young adult population to minimize the age-related degeneration of the tendon, making it possible to investigate these parameters as independent etiological factors.

Several limitations of this study are noteworthy. Since an association between Achilles tendon blood flow and kinematic variables has been shown, measuring limb kinematics would have given this study added value. However, the testing protocol of this large-scale prospective study was already time-consuming, so the FPI was implemented. Furthermore, the implementation of a validated overuse questionnaire such as the Oslo Sports Trauma Research Centre (OSTRC) questionnaire would have added value to this study, as would the weekly workload registration to define the acute-chronic ratio. Another limitation is that the blood flow measurements were performed directly after the running activity since real-time measurement of the blood flow is not possible. Also, blood flow measurements and Achilles thickness measurements were performed in randomized order after running. Since the increase in blood flow after activity is followed by a quick recovery to baseline, the differences in the timing of the blood flow measurement after activity constitute a limitation. However, we added timing of blood flow measurement as a confounder in our statistical analyses, which we believe overcame this limitation. Next, we are aware of the limited number of events used to study several variables, since a general rule is that a Cox model should use a minimum of 10 outcome events per predictor variable. Therefore, after our univariate analyses, we included a limited number of predictors so as not to overfit our Cox model. We should also mention that the general UTC evaluation, whereby we assessed the midportion volume 2 to 6 cm proximal of the calcaneus, was possibly not suitable to detect small structural changes in the tendon. Therefore, assessment of structural changes that are possibly present (eg, hypoechoic regions) rather than assessment of the entire midportion could be more suited as a predictor of further disease. We also acknowledge the homogeneity of our study population of active young adults, which limits the generalization of these findings to other age groups. Nevertheless, this population was targeted to exclude age-related degeneration and represents normal, healthy tendons.

Conclusion

This is the first study to prospectively identify both female sex and the blood flow response after running as significant predictors for the development of AT. Achilles tendon thickness, foot posture, and a general evaluation of the tendon structure, defined by UTC, were not significantly associated with the risk of developing of AT. Possibly, a general evaluation of UTC tendon structure is not suitable to quantify subtle differences in tendon structure that may precede the development of symptoms in a healthy population of young adults.

Footnotes

Acknowledgements

The authors thank Kelly Berckmans and Negar Kooroshfard for their valuable contribution to this paper.

The authors declared that they have no conflicts of interest in the authorship and publication of this contribution.

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