Left ventricular global longitudinal strain as a parameter of mild myocardial dysfunction in athletes after COVID-19

27

28 Whether impaired left ventricular (LV) function contributes to persistent cardiopulmonary 29 symptoms or decreased exercise capacity after COVID -19 remains unclear. The aim of this 30 prospective study was to determine differences in LV global longitudinal strain (GLS) between 31 athletes who did not have a history of LV dysfunction but had a positive COVID-19 test (PCAt) 32 and healthy control (CON) athletes and relate them to symptoms during COVID-19. 33

34 We performed 151 transthoracic echocardiographies in our high-performance laboratory. GLS 35 was determined in four -, two -, and three -chamber views and assessed offline by a blinded 36 investigator in 88 PCAt (35% women) at a median of two months after COVID-19 who trained 37 at least three times per week with more than 20 MET per week and 52 CONs from the German 38 national squad (38% women). 39

40 GLS was significantly lower (GLS -18.53±1.94% vs. -19.94±1.42%, p<0.001) and diastolic 41 function significantly reduced (E/A 1.5 4±0.52 vs. 1.66±0.4 3, p=0.0 20; E`l 0.15±0.04 vs. 42 0.17±0.04, p=0.0 09; E/E'l 5.7 4±1.74 vs. 5.2 2±1.36, p=0.0 24) in PCAt . There was no 43 association between GLS and acute symptoms like resting dyspnea, exertional dyspnea during 44 or after COVID-19, palpitations, chest pain or increased resting heart rate. However, there was 45 a trend toward lower GLS in PCAt with subjectively perceived performance limitation 46 (p=0.054). 47

48 In a cohort of athletes at a median two months after COVID-19, significantly lower GLS and 49 diastolic function were observed, suggesting mild myocardial dysfunction. GLS could be used 50 as a screening element during return-to-sport examinations. 51 52 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 3 Key words 53 Sport; SARS-CoV-2; Deformation imaging, Spe ckle tracking echocardiography ; Exercise 54 Performance 55 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 4

56 Coronavirus Disease 2019 (COVID -19) is a systemic viral infection caused by Severe Acute 57 Respiratory Syndrome -Coronavirus-2 (SARS -CoV-2) that primarily affects the respiratory 58 system but can also cause myocardial damage (1-3). Even supposedly healthy individuals and 59 athletes may be limited by COVID -19 despite a normally good state of health and fitness. 60 Studies of elite athletes have shown that infection is often mild (46-82%) or asymptomatic (16-61 58%) (4-7). The most commonly reported symptoms are fever, headache, limb and muscle pain, 62 flu symptoms, fatigue and dyspnea (4, 8, 9). In rare cases (1-3%), myocarditis may occur (10, 63 11). Most athletes can return to competitive and amateur sports after a training break adapte d 64 to the existing symptoms and, if necessary, a return -to-sport examination (12-14). However, 65 having passed through COVID-19 does not necessarily imply complete recovery to the original 66 health or performance status. Symptoms may persist for weeks and months after symptomatic 67 as well as asymptomatic disease progression or reappear with latency (15). Approximately 20-68 30% of SARS -CoV-2 positive patients in the normal population (16, 17) and probably fewer 69 athletes (1.2-40%) still have symptoms after acute infection (18, 19). Fatigue, neurocognitive 70 impairment, exertional dyspnea (20 -30%), exertion al and non -exertional chest pain or 71 palpitations (16%) may arise or persist after COVID-19 (13, 17, 20). Acute as well as persistent 72 symptoms can lead to athlete performance loss and even career termination if athletes are 73 unable to return to their pre-COVID-19 performance. 74 In this context, impaired left ventricular (LV) function could contribute to persistent symptoms 75 and reduced performance. However, larger multicenter studies of return to sport in competitive 76 athletes suggest cardiac involvement in only a few cases (4, 10, 11, 21) . If cardiac symptoms 77 exist during and/or after infection, a return-to-sport examination with echocardiography should 78 be performed (13). Here, LV function can be assessed with speckle-tracking echocardiography 79 (STE) in addition to conventional echocardiographic indices (12). Individual studies 80 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 5 demonstrated reduced LV global longitudinal strain (GLS) with preserved Ejection Fraction 81 (pEF) in the setting of acute SARS -CoV-2 infection in hospitalized patients regardless of 82 infection severity (22-24) and in patients recovered from COVID-19 (25-27). There are limited 83 data on changes in LV GLS in athletes after COVID -19. In two studies, GLS was not altered 84 after COVID-19 (28, 29). 85 The aim of this prospective study was, first, to determine differences in LV GLS between 86 athletes who had no history of LV dysfunction but had a positive COVID -19 test (PCAt) and 87 healthy co ntrol athletes (CON). Second, we investigated whether there was an association 88 between GLS and symptoms during COVID -19 to identify athletes in need of more targeted 89 follow-up. 90

91 Study population 92 151 competitive athletes presenting to the Ulm Clinic for Sports and Rehabilitation Medicine 93 underwent transthoracic echocardiography in this prospective single-center cohort study 94 between June 2020 and November 2021. For our evaluation we were able to include 140 95 examinations: 88 athletes with history of a positive COVID-19 test (PCAt) at a median of 2.00 96 months (25% quantile=1.00 months, 75% quantile=5.00 months) after COVID-19 and 52 97 healthy athletes from the German national squad as control group (CON) presenting for annual 98 pre-participation screenings. Inclusion criteria for PCAt were: ≥ 18 years of age , training at 99 least 3 times per week with more than 20 metabolic equivalents of task (MET) per week , 100 positive SARS -CoV-2 PCR test or antibody detection with additional typical symptoms. 101 Exclusion criteria for both groups were: acute or chronic medical conditions that precluded the 102 planned physical examination, acute SARS-CoV-2 infection, refusal of peripheral venous blood 103 sampling, inadequate German language skills and withdrawal from study participation . Fifty-104 seven PCAt (6 5%) responded to questionnaires about symptoms and complaints during 105 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 6 COVID-19, which we included in our analysis. Participants provided written informed consent 106 after being instructed of the study procedures. The study was conducted in accordance with the 107 Declaration of Helsinki and approved by the local ethics committee of the University of Ulm 108 (EK 408/20). 109 110 Echocardiography 111 151 echocardiographic examinations were performed using an EPIQ 7 ultrasound system with 112 a phased-array probe X5-1 (Philips GmbH, Hamburg, Germany). GLS and global radial strain 113 (GRS) were determined in apical four -, two- and three-chamber views in the apical, midline, 114 and basal segments. They were determined offline using TomTec postprocessing software (2D 115 Cardiac Performance Analysis, TomTec Imaging Systems, Unterschleissheim, Germany) by an 116 investigator who was blinded to group assignment. The endocardial contour was manually 117 adjusted. Eleven echocardiographs (7.3%) with impaired image quality and in which GLS and 118 GRS could not be determined in all standardized apical views were excluded. Segments were 119 classified as normal based on GLS if regional GLS was ≤-16.0% and abnormal if ≥-16.0%. A 120 selection of 15 images were reviewed a second time by the same investigator and another time 121 by a second blinded investigator to determine intrarater and interrater reliability. The following 122 parameters were collected: end-diastolic volume (EDV), end -systolic volume (ESV), left 123 ventricular mass , left ventricular Ejection Fraction (LV -EF by biplane LV planimetry by 124 Simpson), fractional shortening (FS ), GLS, GRS, stroke volume (SV) , and resting heart rate 125 (HR). Diastolic function was characterized by E/A ratio, E/E´lateral ratio , E/E'medial ratio, 126 VmaxE, VmaxA and deceleration time (Dec Time). 127 128 Statistical analysis 129 Statistical analyses were performed using R version 4.1.1 (30). Descriptive data are presented 130 as mean (M) ± standard deviation (SD) or as median and 25% quantile and 75% quantile. Group 131 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 7 differences were examined using unpaired-Wilcoxon-Tests. Correlations between GLS and age 132 and BMI were analyzed using the Pearson -correlation coefficient (r) and Spearman’s ρ. 133 Additional analyses comparing the frequency of clinically abnormal GLS values in PCAt and 134 CON were calculated using the phi coefficient. To control for possible confounding variables 135 (BMI, age, sex, HR), linear regression models were performed for the confounding variables 136 separately. A p-value of < 0.050 was considered significant. 137 138

139 Cohort characteristics 140 A total of 88 PCAts and 52 CONs were included in the statistical analysis. The groups did not 141 differ in terms of sex, weight, height, systolic blood pressure or HR. A significant age difference 142 was found between PCAt and CON. BMI and diastolic blood press ure were significantly 143 different between the two groups (Table 1). 144 145 146 147 148 149 150 151 152 153 154 155 156 157 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 8 Table 1: Cohort characteristics subdivided in athletes after COVID-19 (PCAt) and healthy athletes of the German 158 national squad (CON) 159 160 PCAt CON test statistic p-value Number 88 52 Sex (female/male) 31/57 (35%/65%) 20/32 (38%/62%) φ=0.04 0.741 Age (years), median (IQR) 29 (22 – 40) 22 (19 – 28) W=2655.5 <0.010 Weight (kg), median (IQR) 73.3 (64.2 – 84.5) 72.4 (61.4 – 80.9) W=2735 0.212 Height (cm), median (IQR) 176 (168 – 189) 179 (171 – 184) W=3332.5 0.4072 BMI (kg/m2), median (IQR) 22.8 (21.6 – 25.9) 22.7 (20.8 – 24.3) W=2522.5 <0.050 Systolic blood pressure, mmHg, median (IQR) 120 (110 – 125) 120 (110 – 130) W=2746 0.1418 Diastolic blood pressure, mmHg, median (IQR) 80 (70 – 80) 80 (71.25 – 90) W=2559 0.033 HR (bpm), median (IQR) 62 (55 – 68) 62 (56 – 68) W=5709 0.6317 Training volume at least three times per week > 20 MET > three times per week >> 20 MET 161 Abbreviations: W (two-tailed unpaired) Wilcoxon Signed Rank Test or φ Phi-coefficient. IQR interquartile range BMI 162 body mass index HR heart rate bpm beats per minute MET metabolic equivalents of task 163 164 Echocardiographic parameters 165 PCAt showed significantly lower GLS values than CON (Figure 1A). In both groups, GLS did 166 not differ between men and women. Positive associations were found between GLS and BMI 167 (r=0.171, p=0.025) in the total cohort. Intrarater and interrater reliability with r espect to the 168 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 9 GLS measure showed high agreement (intrarater: 0.892 [95%CI, 0.593-0.973]; interrater: 0.794 169 [95%CI, 0.159-0.949]. There was no significant association between GLS and age ( r=0.127, 170 p=0.093), GLS and the time period between examination and infection (r=0.155, p=0.115), 171 GLS and HR (r=0.146, p=0.054) or between GLS and systolic ( r=-0.110, p=0.1646) and 172 diastolic blood pressure (r=-0.06, p=0.483). 173 LV-EF and FS were normal in both groups but signif icantly higher in PCAt (Figure 1B and 174 1C). In PCAt, end -systolic volume was significantly smaller and LV mass was significantly 175 reduced (Table S1). Measured values of diastolic function were within the normal range but 176 there was a significant difference for E/A, E`lateral and E/E´lateral (figure 1D, 1E and 1F). The 177 extent of GLS reduction was closely related to E/A -Ratio (p<0.001) and to VmaxE (p<0.001). 178 There were no significant differences in EDV, stroke volume and GRS between PCAt and CON 179 (Table S1). The results of the comparison between PCAt and CON remained when age, HR, 180 sex or BMI were included as control variables. 181 182 Initial symptoms and correlation analysis with GLS and GRS 183 Symptoms reported during COVID -19 infection were classic symptoms of viral infection: 184 cough (55%), rhinitis (66%), exertional dyspnea (57 %), and subjectively perceived reduction 185 in performance (66 %) compared with maximal performance before COVID -19. Even after 186 infection, exertional dyspnea persisted in 62% (Table S2). GLS and GRS values did not differ 187 between PCAt who reported symptoms during COVID-19 compared with asymptomatic PCAt. 188 (Table S3 and S4). However, there was a trend toward lower GLS in PCAt with subjectively 189 perceived performance limitations, but it was not significant (W=417.0, p=0.057). 190 191 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 10 192 Figure 1 : Differences in left ventricular parameters and diastolic function between athletes after COVID -19 193 (PCAt) and healthy federal squad athletes (CON). A: Global longitudinal strain (GLS) B: Ejection Fraction (EF) 194 C: Fractional shortening (FS) D: E/A ratio E: E`l F: E/E´l. Significant results were presented as follows: * < 0.05 195 ** < 0.01 *** < 0.001 196 197 198

199 Cardiopulmonary symptoms after COVID-19 have been described, but not the influence 200 of disease symptoms on cardiac function . In this prospective, single-center cohort study, we 201 observed significantly lower GLS values and diastolic function in PCAt , suggesting mild 202 PCAt CON 20 40 60 80 100 EF (%) B ✱ PCAt CON 0 20 40 60 80 FS (%) C ✱ PACt CON 0 1 2 3 4 E/A D ✱ PACt CON 0.0 0.1 0.2 0.3 E`l E ✱ ✱ PCAt CON 0 2 4 6 8 10 E/E`l F ✱ PCAt CON -30 -20 -10 GLS (%) A ✱ ✱ ✱ All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 11 myocardial dysfunction which might lead to small but decisive performance losses in 203 competitive sports. 204 Acute SARS -CoV-2 infection in hospitalized patients showed reduced GLS with pEF, 205 regardless of the severity of infection (22-24), but the long-term consequences, e.g., in terms of 206 mortality, incidence of heart failure, or eventual recovery, are still unknown. Lower GLS has 207 also been observed in patients with heart failure and pEF (31). There is limited research on GLS 208 in athletes after COVID -19. Fikenzer et al ., found no echocardiographic GLS differences 209 between eight infected and four un infected elite handball players, but magnetic resonance 210 imaging showed mild signs of acute inflammation/edema in all infected athletes (29). However, 211 the study was very small and limited to male athletes. In our study, ten PCAt with reduced GLS 212 and persistent symptoms received MRI. In three of eight MRI examinations myocarditis was 213 revealed, which is consistent with data from the current literature describing a very low rate (1-214 3%) of myocarditis after COVID -19 (10, 11) . Echocardiographic GLS measurement is a 215 commonly available test and may be useful as an additional parameter in selecting athletes with 216 appropriate clinic for limited capacity MRI examinations (12). Another study showed no 217 COVID-19-mediated GLS differences in 107 elite athletes (23% women) with mild symptoms 218 and 107 randomized healthy athletes. (28). However, in a subset of post-COVID athletes with 219 early diastolic septal flattening, there was a relative decrease in GLS in the free wall segments, 220 suggesting a characteristic feature of pericardial constriction. Concerning the LV-EF, however, 221 our results are in line with Lakatos et al. showing increased LV-EF in PCAt compared with 222 CON. Increased LV-EF can result from reduced training volume, since LV-EF is often low 223 normal (32) or even slightly reduced in athletes (28, 33). Here, longitudinal investigations of 224 GLS and LV-EF in detraining would be necessary. 225 Decreased GLS as an early marker of myocardial dysfunction could potentially 226 contribute to persistent cardiopulmonary symptoms and subjectively perceived performance 227

after COVID -19. We investigated whether symptomatic courses lead to cardiac 228 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 12 sequelae but found no differences in GLS or GRS between symptomatic and asymptomatic 229 athletes. Classic symptoms such as cough, rhinitis, sore throat, exertional dyspnea, and 230 subjectively perceived performance limitations were present in more than half of the P CAt, as 231 reported in several studies (4, 8, 9). Even after infection, exertional dyspnea remained in 6 2% 232 of PCAt, which is significantly more frequent than 20-30% reported in the literature (13, 20). 233 Reasons for this could be: First, athletes might notice small changes in form of exerti onal 234 dyspnea earlier and more than non -athletes or secondly, it could be that mainly athletes with 235 complaints presented themselves to our department. However, there was a trend toward lower 236 GLS in PCAt with subjectively perceived performance limitation . A direct effect of reduced 237 GLS on performance does not yet exist and should be evaluated in further studies. To our 238 knowledge, this is the first study to evaluate individual symptoms rather than severity of course. 239 Post-COVID patients with significant functional impairment were more likely to have impaired 240 GLS or cardiovascular comorbidities whereas those with mild to moderate functional 241 impairment had no cardiovascular changes (25). Similar results were obtained by Mahajan et 242 al., who described increasing impairment of GLS in mild (13.1%), moderate (44%), and severe 243 (90%) disease (26). These patients were older than our cohort of athletes and had concomitant 244 cardiovascular diseases such as hypertension and diabetes mellitus. Furthermore, they were 245 examined earlier ( 30-45 days after infection ) than ours , so improvement of LV dysfunction 246 cannot be excluded. However, our results argue against a temporal compon ent: There was no 247 significant association between GLS and the time period between examination and infection, 248 which could indicate a possible stable long-term decrease in GLS in PCAt. 249 In our study, there is no positive correlation between GLS and age in the overall cohort. 250 Zghal et al . found a decrease in GLS with age with no change in LV -EF (34). In the Danish 251 City of Copenhagen Heart Study GLS changed differently with age in men and women , with 252 men having lower mean values and lower reference limits for all exercise parameters . 62% of 253 participants were female and older with an age of 46±16 years compared with our study, which 254 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 13 had 45% women and ages of 31.44±12.62 (PCAt) and 24.69±7.89 (CON) years, respectivel y 255 (35). In our study, GLS did not differ between men and women in both the PCAt and CON 256 groups. Although diastolic blood pressure was significantly different between PCAt and CON, 257 there was no association between GLS and systolic or diastolic blood pressure. Blood pressure 258 levels correlate d with GLS (36, 37) , and GLS was significantly re duced in patients with 259 hypertension compared with normotensive control subjects (38). Due to the specific athlete 260 clientele, the variance of the blood pressure values is low, which is accompanied by a limited 261 interpretability of the correlation. There was a positive association between GLS and BMI in 262 our study. Impairment of LV-EF and GLS by overweight and obesity is also known from other 263 studies (39-41). Parameters of diastolic function were within the normal range in our studied 264 athletes but were significantly reduced in PCAt. Some authors indicate that diastolic function 265 is normal or decreased in athletes (42, 43) but may also be supran ormal in trained endurance 266 athletes compared with untrained individuals (44). According to the study by Galderisi et al ., 267 the extent of GLS is closely related to diastolic function (43). We also demonstrated a 268 correlation of GLS with E/A ratio and VmaxE. Thus, routine determination of diastolic function 269 may be an initial clue to possible LV dysfunction and should be followed by determination of 270 GLS at the latest in case of abnormalities. 271 272 Strengths and Limitations 273 This study is limited by the cross-sectional design, as no prior strain values of PCAt and CON 274 were available. Therefore, it cannot be excluded that reduced strain values did exist preliminary 275 or are due so sport-related adjustments. Because of the nature of this study, the time after SARS-276 CoV-2 infection differed between subjects, and heart function may have already improved or 277 worsened during infection perhaps as a result of detraining. However, there was no significant 278 correlation between GLS and the time between examination and infection. The clearly defined 279 population of study participants, consisting of athletes, limits the generalizability of the results 280 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 14 for the general population, but on the other hand allows an assessment of a specific group. The 281 difference in training volume between th e two groups may affect our results because GLS is 282 sport-dependent. However, even when the groups differed significantly in age and diastolic 283 blood pressure, no significant association between GLS and age and GLS and diastolic blood 284 pressure was found. Although the GLS determination can be software and investigator 285 experience dependent, our results show high intrarater and interrater reliability. It should be 286 emphasized that we achieved a meaningful case number of athletes for a single -center study. 287 Finally, although an association between COVID -19 and the occurrence of pathological 288 examination findings up to myocarditis is suggested, direct evidence is still lacking. 289 290

291 Significantly lower GLS and diastolic function in PCAt compared to healthy peers 292 suggests mild myocardial dysfunction after COVID -19, potentially contributing to decreased 293 training and competition performance. When it comes to success and failure, winning medals 294 or top placings, small differences in performance can be decisive. T herefore, myocardial 295 damage, in addition to factors such as lack of training can be detrimental to success. Therefore, 296 determination of GLS as a screening element for early detection of left ventricular dysfunction 297 could be part of the return-to-sport examination. Long-term observations in athletes as well as 298 in the general population are needed to evaluate the impact of COVID-19 on cardiac function 299 and performance limitation. 300 301 302 303 Supplementary Data 304 Table S1: Echocardiographic parameters subdivided in athletes after COVID -19 (PCAt) and 305 healthy athletes of the German national squad (CON) 306 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 15 Table S 2: Symptoms during COVID -19 in athletes after COVID -19 (PCAt) presented as 307 absolute values and relative frequencies 308 Table S3: Symptoms during COVID-19 in athletes after COVID-19 (PCAt) in correlation with 309 GLS. 310 Table S4: Symptoms during COVID-19 in athletes after COVID-19 (PCAt) in correlation with 311 GRS. 312 313 Funding 314 This work was supported primarily by the University Hospital Ulm and funds from the German 315 Federal Institute for Sport Science, Cologne by resolution of the German Bundestag [ZMVI4 -316 070106/20-23]. 317 318 Conflicts of Interest: Nothing to Disclose. 319 320 Data Availability 321 The data underlying this article will be shared on reasonable request to the corresponding 322 author. 323 324 Author Contributions 325 J.S. and J.M.S. responsible for conceptualization; M.A. and J.S. performed measurements, L.M. 326 and M.A. analyzed data; J.S., M.A., L.M. and J.M.S. interpreted results of data and 327 examinations; J.S. and L.M. prepared figures; J.S. drafte d manuscript; L.M., J.K i., J.K. and 328 J.M.S. edited and revised manuscript; J.S., L.M., J.K. and J.M.S. approved final version of 329 manuscript. 330 331 332 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for thisthis version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.14.23287258doi: medRxiv preprint 16

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