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Biochemical cartilage alteration and unexpected signal recovery in T2* mapping observed in ankle joints with mobile MRI during a transcontinental multistage footrace over 4486 km
Address correspondence and reprint requests to: U.H.W. Schütz, Department of Diagnostic and Interventional Radiology, University Hospital Ulm, Albert-Einstein-Allee 23, Ulm D-89081, Germany.
The effect of ultra-long distance running on the ankle cartilage with regard to biochemical changes, thickness and lesions is examined in the progress of a transcontinental ultramarathon over 4486 km.
Method
In an observational field study, repeated follow-up scanning of 22 participants of the TransEurope FootRace (TEFR) with a 1.5 T MRI mounted on a mobile unit was performed. For quantitative biochemical and structural evaluation of cartilage a fast low angle shot (FLASH) T2* weighted gradient-echo (GRE)-, a turbo-inversion-recovery-magnitude (TIRM)- and a fat-saturated proton density (PD)-weighted sequence were utilized. Statistical analysis of cartilage T2* and thickness changes was obtained on the 13 finishers (12 male, mean age 45.4 years, BMI 23.5 kg/m²). None of the nine non-finisher (eight male, mean age 53.8 years, BMI 23.4 kg/m²) stopped the race due to ankle problems.
Results
From a mean of 17.0 ms for tibial plafond and 18.0 ms for talar dome articular cartilage at baseline, nearly all observed regions of interest (ROIs) of the ankle joint cartilage showed a significant T2*-signal increase (25.6% in mean), with standard error ranging from 19% to 33% within the first 2500 km of the ultra-marathon. This initial signal behavior was followed by a signal decrease. This signal recovery (30.6% of initial increase) showed a large effect size. No significant morphological or cartilage thickness changes (at baseline 2.9 mm) were observed.
Conclusion
After initial T2*-increase during the first 2000–2500 km, a subsequent T2*-decrease indicates the ability of the normal cartilage matrix to partially regenerate under ongoing multistage ultramarathon burden in the ankle joints.
Societal life style changes in the last 20 years have created a distinct divide with one group reaching for higher and higher levels of fitness and the other resigning to a more sedentary daily life. There is abundant research on consequences of obesity and sedentary lifestyles for the human body and lower extremity joints in particular
The TransEurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486 km transcontinental ultramarathon.
where the participants were continuously monitored using a mobile magnetic resonance imaging (MRI) traveling along on a semitrailer truck offered a unique, once in a life time opportunity for investigating the physiological responses to extreme contiguous 64 day exercise without any day of rest. How much exercise is beneficial for the human body and where is the limit for physiological adaptation of the ankle joint, if there is one, when human beings are running more than 100 marathons, one after another? Only very few data are published concerning the abnormalities and functional adaptation of the ankle joint (tibiotalar joint; TTJ) cartilage to mechanical loadings
, nothing is known about the consequences of ultra-long distance running for the cartilage of the lower extremity joints. In this setting, a strategic decision had to be made for just one of the “quantitative cartilage mapping techniques” to fit the severe time constraints, as whole body, brain and cardiovascular studies also were performed. The ankle joint is uniquely designed for repetitive and high biomechanical loading on a much smaller surface area than the knee with a “mortise” type fit. Furthermore, the articular cartilage is much thinner than in the knee
. Therefore, to obtain reasonable signal to noise and the necessary resolution to image a thin, curved small structure in a short acquisition, T2* relaxation time measurements were chosen
. This measurement offers inherently higher signal-to-noise ratio and robustness when compared to other options such as T2, T1rho, chemical exchange saturation transfer (CEST), delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), Na measurements etc
, unless a pre-existing injury is present. Our goal in this study was to explore the physiological adaptive capacity of the TTJ cartilage under conditions of extreme wear and address the question how much is too much?
Method
Of the 67 runners in the 4486 km ultramarathon, 44 volunteers who were officially accepted as TEFR participants by the organizers
The TransEurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486 km transcontinental ultramarathon.
were included in the scientific TEFR project. The local ethics committee approved the study in accordance to the Declaration of Helsinki. The project included multiple MRI studies, such as brain, cardiac, vascular and musculoskeletal imaging at baseline and four consecutive time points approximately every 900 km in the race. Musculoskeletal imaging was randomized to 22 runners each (20 male, two female) in a knee MRI (reference) and an ankle/foot MRI group, results reported here, respectively
The TransEurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486 km transcontinental ultramarathon.
. All 22 randomly selected volunteers in the ankle cohort met the inclusion criteria which were official acceptance as a participant at the TEFR by the organizers
The TransEurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486 km transcontinental ultramarathon.
scanning. Subsequently, 13 (59.1%) of the 22 participants in the ankle/foot MRI study group finished the race with a baseline and all four consecutive MRI data time points necessary for the data analysis. Main reason for prematurely voluntary withdraw from race were stress reaction to the lower extremity soft tissues including the muscles, tendons, bones and subcutaneous tissues unrelated to the ankle or foot joints (6). The data of the study subjects (13 finisher/9 non-finisher) at baseline were: mean age 45.4/53.8 years (SD 10.7/11.3, range 27–62/36–68), male 12/8 (92.7/88.9), body mass (BM) 73.0/67.9 kg (SD 11.3/11.3, range 51.9–94.2/49.2–81.8), body mass index (BMI) 23.4/23.5 kg/m² (SD 2.5/3.0, range 20.5–29.1/19.2–28.3). Age, gender, BMI and clinical alignment of the lower extremity joints showed no relevant differences between study subjects and non-participants
The TransEurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486 km transcontinental ultramarathon.
MRI data were acquired with a mobile 1.5 T MR scanner (Avanto™, Siemens Ltd., Erlangen), which was mounted on a MRI-semitrailer truck traveling with the runners throughout whole TEFR. Their ankles were scanned consecutively using a table fixed, 8-channel ankle and foot array coil with a boot-like design ensuring a standardized foot position. MRI scanning was planned at baseline (t0) within the last 4 days before start and roughly every 900 km (±211.5 km) measurement interval (MI: t1–t3) during the race and t4 representing the endpoint.
For T2*-mapping a sagittal fast low angle shot (FLASH) T2* gradient-echo (GRE) sequence was used: flip angle (FA) 60°, echo times (TE) 4.5/12.2/19.9/27.7/35.4 ms, repetition time (TR) 1010 ms, slice thickness (ST) 2.5 mm, field of view (FOV) 182.25 cm², pixel size (PS) 0.178 mm² (in plane resolution). For quantitative biochemical cartilage analysis T2*-relaxation times were obtained from online reconstructed T2*-maps by using a pixel wise, monoexponential nonnegative least squares fit analysis (syngo™ MapIt; Siemens Ltd.)
. For detection of soft tissue pathology a turbo inversion recovery (TIRM) sequence was utilized in the sagittal plane: FA 140°, TE 60 ms, inversion time 120 ms, ST 2 mm, FOV 900 cm², PS 0.343 mm². Additional proton density weighted fat saturated (PDfs) sequence was obtained if a suspected subchondral signal abnormality was detected: FA 150°, TE 32 ms, TR 5830 ms, ST 3 mm, FOV 256 cm², PS 0.172 mm².
The articular cartilage of the ankle joint was defined as normal if the cartilage thickness was preserved, no cartilage signal alterations and no superficial and deep cartilage defects or fissures were present on the respective morphological imaging sequences (TIRM, PDfs, T2*-GRE).
For image post processing three sagittal slices through TTJ centered between the medial and lateral margins of the talar dome and two additional slices 8.2 mm medially and laterally, respectively. Six regions of interest (ROIs) for analysis of mean T2*-values were manually drawn on the three slices to cover the entire tibial plafond and talar dome cartilage: tibial-medial, tibial-central, tibial-lateral, talar-medial, talar-central, talar-lateral [Fig. 1(B)]. Cartilage thickness was measured in the center of the anterior, mid and posterior third of each of the three sagittal slices [Fig. 1(C)]. All measurements were done by three experienced musculoskeletal radiologists (UHS, DS, BC).
Fig. 1MR-image post-processing for quantification of thickness and T2* relaxation time of TTJ cartilage: A: sagittal FLASH T2*w GRE: (1) tibia, (2) talus, (3) calcaneus, (4) navicular, (5) cuboid, (6) ankle joint, (7) subtalar joint, (8) talonavicular joint, (9) calcaneocuboidal joint. B: fused colored T2* GRE map (syngo™ MapIt fusion technique): colored visualization of T2* in tibial plafond and talar dome cartilage of the ankle joint. C: cartilage thickness [mm] measurement of ankle joint (anterior, central and posterior in each slice).
. In lesions greater Outerbridge grade 1 the ROI for quantitative T2*-analysis was drawn in the subjacent cartilage slice.
For data documentation and statistical analysis Microsoft™ Office Excel™ (Microsoft Inc.) and SPSS™ (IBM™ Statistics, SPSS Inc.) were utilized, respectively.
The absolute thickness values are presented (Table I) as means and standard deviation (SD) with min and max. The T2*-values are presented as absolute values and relative differences to baseline for the finisher cohort.
Table IThickness measurements (at baseline) and throughout TEFR (t0–t4): mean (SD), range (n = 13)
For determination of intraobserver precision of ROIs, mean T2*- and thickness-values, all measurements of the right side were performed at baseline (t0) and at a mean interval of 3 weeks by one investigator (UHS). For interrater reliability baseline measurements of two radiologists (UHS and DS) were compared. For precision calculation the 95% limits of agreement (LOA: mean difference ± 1.96 SD)
A tests P-value of 0.05 indicated significance. For testing on differences between T2*-relaxation times of tibial plafond and talar dome ROIs within the same slice a t test for independent variables was used. Differences between T2*-relaxation time of ROIs within the same cartilage layer at the same time point were calculated by a 1-way analysis of variance (ANOVA) without repeated measurements. To analyze significant changes of T2*- and thickness-values between t0 and MI (t1–t4) during TEFR a 1-way ANOVA for repeated measurements utilized. Given the longitudinal nature of the test data, a general linear model for repeated measurements was applied. For correction of accumulation of the alpha level due to multiple testing a Bonferroni-procedure was applied. The precondition sphericity was proven by the Mauchly-Test. To determine a trend of T2*-value curves in progress of TEFR significance of innersubject effects of the ANOVA were calculated. To determine significant value differences at the end of TEFR (t4) to any maximal change (peak) during exercise (t1–t3) compared to baseline, a paired (two-tailed) samples t test with calculation of the effect size according to Cohen
If relevant changes in the course of TEFR were found, relationship to influencing cofactors of running burden (Table I) and BM was proven with a specific regression analysis using a linear mixed model for fixed effects.
Results
Combined tibial plafond and talar dome mean cartilage thickness ranged from 2.4 to 3.5 mm and there was no significant change in articular cartilage thickness during the race (Table I).
Drawn ROI sizes ranged from 32.3 mm² (lateral tibial) to 38.0 mm² (medial tibial). Intra- and interrater analysis showed high agreement for drawn ROI sizes with 7.5% (2.7 mm²) and 8.3% (3.0 mm²), for cartilage thickness with 5.5% (0.16 mm) and 6.3% (0.19 mm), and for T2* values with 3.1% (0.5 ms) and 3.3% (0.6 ms) respectively. The intra-and interrater reliabilities (λ) were high for all ROI sizes ranging from 0.962 to 0.991 and 0.965 to 0.992, for measured thickness ranging from 0.975 to 0.991 and 0.969 to 0.990 and for T2* values ranging from 0.995 to 0.998 and 0.994 to 0.998 at baseline respectively.
In the finisher cohort the mean baseline T2*-values for the right and left ankle were 16.1 ms (SD 2.4) and 17.8 ms (SD 2.7) for tibial plafond and 17.5 ms (SD 3.1) and 18.4 ms (SD 3.3) for talar dome cartilage, respectively. Figure 2 demonstrates the mean, confidence interval (CI) and percentiles for each ROI, the talar dome revealed a higher T2*-value (1.1% in mean) compared to the tibial cartilage at baseline, but this was only significant in the central ROIs at t1 and t2, in the medial ROIs of the left side throughout total TEFR (t1–t4) and on the right side only at t2 (Table II). Tibial and talar cartilage T2*-values combined were significantly different on the left side at t2, t3, and t4 and on the right only at t2.
Fig. 2T2*-mapping of TTJ (relaxation time): Absolute values of measures of variation (nF = 13).
The relative changes of T2*-values compared to baseline during TEFR revealed a T2*-increase between t0 and t2 in all regions. This increase amounted 27.7% (tibial 26.1%, talar 29.5%) one the right and 23.5% (tibial 18.4%, talar 28.8%) on the left in mean. Total standard error of the signal increase ranged from 22.3 to 33.0% on the right and 18.9 to 28.0% on the left (Fig. 3) and was significant for all ROIs throughout TEFR, with exception of the left central tibial ROI (Table III). Subsequently, T2*-signal decreases in all ROIs: mean 10.1% (10.8% tibial, 9.4% talar) on the right and 6.2% (6.0% tibial, 6.4% talar) on the left (Fig. 3). With the exception of the right medial talar ROI–(linear) decrease, all other ROI's showed quadratic decrease. All tibial and talar ROIs, as well as combined ROI's show at least a medium to high effects size of T2*-value decrease (Table III).
Fig. 3T2*-mapping of TTJ: Relative changes of T2* relaxation times of single and aggregated segments compared to start (finisher group; nF = 13).
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
Significant quadratic trend of T2*-signal curve shows high test power.
ROIs: regions of interest (tibial-medial, tibial-central, tibial-lateral, talar-medial, talar-central, talar-lateral).
Bold fonts show significance (P-values).
∗ “Greenhouse-Geisser” correction procedure was used.
† Significant T2*-relaxation time decrease after initial increase with large effect size (Cohen's d > 0.8) at the end of TEFR related to max. (peak) in the first part of TEFR.
‡ Significant quadratic trend of T2*-signal curve shows high test power.
On the right a significant dependency between total distance run, total run time and number of finished stages till time of MRI scanning could be shown for all combined tibial and talar ROI's and all talar ROIS's (Table IV). On the left such dependencies were only detectable for the medial tibial ROI, whereas the all combined tibial and talar ROI's were dependent on number of finished stages till time of MRI also (Table IV). The distance run of the stage at the day of mobile MRI had relevant influence on T2*-value measurements of the right combined tibial and talar ROI's, all talar ROI's and the talar-central ROI (Table IV). On the left side this was only detectable for the tibial-lateral ROI (Table IV). BM and outcome parameters cartilage thickness and T2* showed no significant relationship at any measurement.
Table IVAnalysis on significant relationships between T2* values [ms] and time of mobile MRI measurements (test of fixed effects – linear mixed models)
Side
ROIs and total joint
Stage no. at time of MRI [n]
Total distance run [km]
Total run time [hrs]
Distance run since last MRI [km]
Run time since last MRI [hrs]
Stage distance at day of MRI [km]
Stage run time at day of MRI [hrs]
Time gap between stage finish and MRI [hrs]
Right
Tibial-lateral
0.336
0.372
0.364
0.266
0.905
0.207
0.416
0.681
Tibial-central
0.286
0.270
0.207
0.273
0.669
0.285
0.571
0.483
Tibial-medial
0.029
0.028
0.039
0.142
0.295
0.166
0.094
0.016
Talar-lateral
0.044
0.042
0.060
0.083
0.752
0.072
0.192
0.143
Talar-central
0.018
0.007
0.016
0.036
0.246
0.003
0.026
0.061
Talar-medial
0.550
0.552
0.450
0.890
0.163
0.153
0.167
0.268
Tibial all
0.072
0.069
0.068
0.149
0.884
0.117
0.186
0.118
Talar all
0.049
0.048
0.049
0.117
0.211
0.004
0.043
0.060
Total joint
0.049
0.049
0.049
0.123
0.430
0.028
0.066
0.071
Left
Tibial-lateral
0.079
0.078
0.105
0.011
0.152
0.029
0.087
0.490
Tibial-central
0.957
0.970
0.974
0.614
0.559
0.660
0.297
0.528
Tibial-medial
0.012
0.012
0.009
0.017
0.150
0.150
0.239
0.914
Talar-lateral
0.314
0.297
0.347
0.190
0.670
0.707
0.884
0.716
Talar-central
0.128
0.127
0.158
0.113
0.145
0.141
0.094
0.051
Talar-medial
0.206
0.217
0.177
0.193
0.067
0.171
0.282
0.370
Tibial all
0.066
0.047
0.080
0.036
0.106
0.145
0.384
0.268
Talar all
0.086
0.093
0.089
0.107
0.114
0.191
0.281
0.162
Total joint
0.034
0.106
0.074
0.049
0.052
0.130
0.274
0.115
ROIs: regions of interest (tibial-medial, tibial-central, tibial-lateral, talar-medial, talar-central, talar-lateral).
Subchondral bone marrow abnormalities were identified in two finishers (49 and 60 years). An ill defined area of subchondral posterior tibial bone marrow edema as evidenced by T2-elevation with an Outerbridge grade 1 lesion of the overlying articular cartilage. The osteochondral lesion did not change in size, however, there was a steady increase of the T2* value over time observed. The bone marrow edema showed no relevant changes throughout TEFR [Fig. 4(A) + (B)]. In three subjects (13.6%) a small unilateral subchondral tibial area of bone marrow edema was visible at baseline with no associated cartilage alterations (grade 0) [Fig. 4(C)]. A prominent posterior process of the talus in two subjects remained unchanged during whole TEFR [Fig. 4(D)].
Fig. 4Osteochondral lesions (yellow arrow) in the ankle joint. Sagittal TIRM slices through TTJ: A: of a 59-years-old male finisher (1: baseline, 2: stage 32/2176 km run, 3: stage 53/3669 km run, 4: 8 months after TEFR) B: of a 49-years-old male non-finisher (1: baseline, 2: stage 19/1260 km run, 3:stage 31/2131 km run, 4: stage 53/3669 km run) C: of a 46-years-old male finisher (1: baseline, 2: stage 52/3609 km run) and a 68-years-old female non-finisher (3: baseline, 4: stage 15/1003 km run) D: of a 34-years-old male finisher (1: baseline, 2: stage 18/1192 km run, 3:stage 29/1985 km run, 4: stage 54/3763 km run).
This study provides a unique insight into the response of the TTJ to extreme physical strains of a contiguous 64-day 4486 km ultramarathon. Regarding our first hypothesis, that the normal ankle joint can withstand extreme physical loading, our study revealed three significant observations.
First, upon morphologic evaluation of the MR images of the ankle no significant pathology was detected in the runners, which had no pre-existing abnormalities. Specifically, the cartilage of the talar dome and the tibial plateau remained intact over the entire time course of the race; there was no evidence of subchondral bone marrow edema or significant joint effusion. None of the runners were eliminated from the study because of subjective or radiographic evidence of ankle pathology. This observation is in keeping with statistics on prevalence of ankle osteoarthritis (OA), which is about 8–10 times less frequent than knee OA
. While all joints are prone to develop OA over time, differences in joint kinetics, cartilage thickness and mechanical properties may result in different degrees of resilience to degeneration. The relative resilience of the native ankle mortise is attributed to its high degree of congruency and associated stability, the thin articular cartilage of the TTJ was found to be withstanding much higher forces of loading than in the knee
Second, the morphometric measurements of mean cartilage thickness revealed no significant change over the course of the race. Measurements of cartilage thickness with MRI are precise and reproducible
. These findings provide further evidence of specific anatomical and biomechanical properties in the ankle as a primary rolling joint with congruent surfaces making the TTJ less susceptible to osteoarthritic changes and more resilient than other joints
Age-related changes in the tensile properties of human articular cartilage: a comparative study between the femoral head of the hip joint and the talus of the ankle joint.
Third, while conventional MR based morphological assessment and measurements revealed stability over the entire race, quantitative T2* measurements allowed insight into the adaptive capacities of the most important structure for load bearing and load dissipation, the articular cartilage. It is well established, that mechanical loading of the articular cartilage regulates homeostasis and normal tissues remodeling. The two components that enable the tissue to withstand compressive stress are a liquid and a multicomponent solid collagen and hydrophilic proteoglycan (PG) phase. Water, the most abundant component in conjunction with free mobile cations greatly influence the mechanical behavior of articular cartilage
via the Donnan osmotic equilibrium. T2* measurement is most sensitive to changes in free water content and collagen orientation with an additional component introduced by susceptibility changes otherwise refocused in T2-mapping
. Most of the water occupies the interfibrillar space of the extracellular matrix and it is believed that approximately 70% of the water is free to move when loaded by compressive forces
is, in turn resisted and balanced by tension developed in the collagen network according to Starling's law. Permeability decreased exponentially as function of both increasing compressive strain as well as increasing fluid pressure
; an immediate adaptive mechanism with loading and unloading, by which decreased permeability allows an overall increase of free water within the articular cartilage as long as the collagen network and PGs can structurally withstand the increasing fluid pressure.
Immediate T2/T2*-decrease and recovery
With cyclical loading of cartilage, as it occurs in running, tissue deformation likely produces an increase in anisotropy of superficial collagen fibers and a concomitant decrease in free cartilage water which leads to lower T2-values on the post-exercise studies. The results of Mosher et al.
and other investigators indicated that this immediate T2-response to running or other physical load is not influenced by age or level of physical activity. During unloading of chondrocytes complete recovery of all structural deformation was observed after 30 min
. In our investigation such immediate T2-decreases could not be detected since T2* data were acquired at least 45 min after unloading and first data points were obtained after a mean distance run of 1000 km when the effects of long time running masked the initial T2-response.
Long distance T2/T2*-increase
After 1000 km of running our data revealed a significant mean T2*-elevation up to 23.5–27.7% in all areas of the ankle cartilage (Fig. 3) with the exception of the left tibial central ROI (Table III), where the baseline T2*-value was already high. Forty-eight hours after a marathon Luke et al.
High-field magnetic resonance imaging assessment of articular cartilage before and after marathon running: does long-distance running lead to cartilage damage?.
found not only significantly higher T2-values but also increased T1ρ values in all articular cartilage of the knee (P < 0.01) except the lateral compartment, postulating a relative decrease of GAGs leading to more free water in the matrix
Functional ankle instability as a risk factor for osteoarthritis: using T2-mapping to analyze early cartilage degeneration in the ankle joint of young athletes.
Osteoarthritis Cartilage.May 2014; ([Epub ahead of print])
, for different reasons. If the overall environment of the chondrocytes is impaired, the excessive fluid pressure will lead to structural changes of cartilage fibrillation, PG loss, and loss of collagen network organization which has been shown in a long-term (1-year) program of running exercise (up to 40 km/day) in the knee and humeral head cartilage of young dogs
. Since no structural and morphometric changes were observed, the slow, but steady increase of T2 in our data over the course of the first 2000–2500 km, could be explained by changes in permeability and respective ion flow reaching a new equilibrium after every run. As increasing hydrostatic pressure up-regulates PG and type II collagen mRNA expression
MRI has not yet been utilized before to probe human cartilage properties beyond a single marathon. A significant T2-increase within the knee cartilage was observed 48 h after a single marathon, which recovered to baseline levels after 3 months
High-field magnetic resonance imaging assessment of articular cartilage before and after marathon running: does long-distance running lead to cartilage damage?.
. Surprisingly, when ultra-marathon runners in our study continued beyond 2000–2500 km a significant T2*-decrease of about 6–10% occurred, which approximates one third of the primary signal increase. Animal experiments have shown that load bearing exercises minimize the development of OA, increases PG content and cartilage thickness in rodent models
After moderate running (1 hr/4 km per day more than 15 weeks) an increase of compression stiffness and GAG-content was observed in young canine patellae and lateral femoral condyles
observed no differences of the biochemical and mechanical qualities of the joint cartilage between both groups, the experiments of Lapvetelainen et al.
More knee joint osteoarthritis (OA) in mice after inactivation of one allele of type II procollagen gene but less OA after lifelong voluntary wheel running exercise.
with long distance running found less knee OA in running knockout mice than sedentary mice. They demonstrated that ultra-long physical activity does not predispose normal mice to OA
More knee joint osteoarthritis (OA) in mice after inactivation of one allele of type II procollagen gene but less OA after lifelong voluntary wheel running exercise.
Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: a four-month, randomized, controlled trial in patients at risk of osteoarthritis.
measured an increase of GAG in the weight-bearing posterior medial femoral condyle following moderate exercise (1 hr exercise, 3 times weekly for 4 months). Tiderius et al.
found in a cross-sectional study with elite runners and untrained volunteers, that human knee cartilage adapts to exercise by increasing the GAG-content using dGEMRIC. The increased concentration of PGs has been shown to impede hydraulic fluid flow
. This mechanism shields the collagen-PG matrix from high stresses.
Ultra-long distance T2/T2*-increase without recovery
With respect to the second question, how much exercise is too much, our observations are significant, when considered in the context of the existing data. Development of ankle OA is intimately related to instability and incongruity caused by trauma
. The impact of traumatic injuries to the tibial plafond, fibula fractures and mainly ankle sprains involving the anterior talofibular ligament (ATFL) or high ankle ligaments leading to OA in up to 70–78% of the patient's
. Within the cohort of runners in this study, there were only two preexisting low grade osteochondral lesions, which on conventional MR imaging did not change appearance, however revealed a steady increase in T2* values, likely evidence of increased swelling, lacking the recovery phase observed in the ankles without pre-existing injuries.
Limitations
There are major limitations in our study, the small number of runners, the lack of complementary quantitative cartilage mapping sequences, which could not be applied due to severe time and study constrains. Specifically, the selective quantitative information on GAG content is missing for more definitive interpretation. However, negative charge density measurements using dGEMRIC, Na or GAG-CEST have their known significant limitations. T1rho (adiabatic or spin-lock) allow detection of PG contributions, but are not selective
. Depth dependence of T2* could not be analyzed in this study due to the thin ankle cartilage. The stage distance run (in km) at the day of MRI measurements influenced T2*-values in some ROIs. It must be assumed that the immediate T2*-decrease based on an increase in collagen fiber anisotropy and the concomitant free cartilage water
exchange were present in parallel to the mechanism of long distance T2-increase. This “masking” effect on the slower T2*-increase is difficult to estimate quantitatively. The time elapsed between stage finish and MRI had no correlation with the data. Other confounders, which were related to performance, had only limited and inconsistent influence on the results (Table IV), they were not adjusted to confounders. T2* data were adjusted to age, regional variation, injuries as confounding factors. This study is subject to a possible selection bias regarding experience in ultra-running before TEFR, however, the influence on results is difficult to assess. Another bias regarding generalizability of our results may be the fact, that non-finisher were 8 years older than finisher.
In conclusion, there are at least three distinct time domains, in the complex adaptation to loading of the cartilage; immediately during and after mechanical loading free water will be trapped or released from the articular cartilage via fast permeability changes. As no structural and morphometric changes were observed, the slow, but steady increase of T2 in our data over the course of the first 2500 km, could be explained by changes in permeability and respective ion flow reaching a new equilibrium after every run. As increasing hydrostatic pressure up-regulates PG and type II collagen mRNA expression
subsequent higher PG content shifts the free fluid back into the PG and collagen bound compartment, the ultra-slow adaptive regime, where T2* will slowly decrease and recover. In cartilage regions with underlying pre-existing osteochondral abnormalities the recovery phase could not be observed in our study, to the contrary, T2* continued to increase over the entire race. As running was an important means for survival from an evolutionary point of view, our findings indicate that the human ankle indeed appears to be resilient to ultra-long distance running, unless a pre-existing injury exists.
Contributions
All authors of this manuscript had substantial contribution to conception and design or acquisition, analysis and interpretation of data; all revised it critically for important intellectual content and did final approval of the version to be published:
Schütz UHW conceived the study (conception and design), implemented the project (including administrative, technical and logistical support), obtained the funding, participated in the data collection (MRI measurements), data assembly and data evaluation with statistical analysis and drafted the article. Ellermann J gave critical revision of the article for important intellectual content and did final approval of the article. Schoss D participated in the data evaluation. Wiedelbach H participated mainly in the data collection (MRI measurements) and in the implementation of the project. Beer M gave critical revision of the article for important intellectual content and did final approval of the article. All authors read and approved the final manuscript. Billich C participated in the implementation of the project (including administrative, technical and logistical support), in the data collection (MRI measurements) and in the implementation of the project (including administrative, technical and logistical support).
Schütz UHW ([email protected]) takes responsibility for the integrity of the work as a whole, from inception to finished article.
Role of funding source
This work is supported in part by the German Research Association (DFG: “Deutsche Forschungsgemeinschaft”), under Grants SCHU 2514/1-1 and SCHU 2514/1-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.
Competing interests
The authors declare that they have no financial or non-financial competing interests. There are no financial or non-financial competing interests of other people or organizations influencing our interpretation of data or presentation of information.
Acknowledgments
We would like to thank all the athletes of TEFR who took part at this project. Considering their immense physical and mental stresses they showed an extraordinary compliance on every day of the race.
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