Objective: To assess the potential therapeutic role of exercise on health-related quality of life, assessed by the Pediatric Outcomes Data Collection Instrument (PODCI), coronary flow reserve (CFR), cardiac function, cardiorespiratory fitness, and inflammatory and cardiac blood markers in multisystemic inflammatory syndrome in children (MIS-C) patients. Methods: This is a case series study of a 12-wk, home-based exercise intervention in children and adolescents after MIS-C diagnosis. From 16 MIS-C patients followed at our clinic, 6 were included . Three of them withdrew before the intervention and served as controls. The primary outcome was health-related quality of life, assessed PODCI. Secondary outcomes were CFR assessed by 13N-ammonia PET-CT imaging, cardiac function by echocardiography, cardiorespiratory fitness, and inflammatory and cardiac blood markers. Results: In general, patients showed poor health-related quality of life, which seemed to be improved with exercise. Additionally, exercised patients showed improvements in coronary flow reserve, cardiac function, and aerobic conditioning. Non-exercised patients exhibited a slower pattern of recovery, particularly in relation to health-related quality of life and aerobic conditioning. Conclusions: Our results suggest that exercise may play a therapeutic role in the treatment of post-discharge MIS-C patients. As our design does not allow inferring causality, randomized controlled trials are necessary to confirm these preliminary findings. Coronavirus disease 2019 (COVID-19) has impacted children and adolescents, with most cases being mild or asymptomatic ,4,5.The cardiovascular system is the most impacted one 80%), followed by hematologic 76%), mucocutaneous (74%), and respiratory (70%) systems [%, mucocu0%, folloRecently, we observed reduced coronary flow reserve (CFR) and impaired cardiopulmonary exercise capacity in a small cohort of MIS-C survivors . CFR is To date, there is limited evidence on the management of MIS-C complications. In this scenario, exercise emerges as a safe and non-expensive tool that could be useful to rehabilitate MIS-C patients, potentially offsetting persistent impairments in cardiovascular function and physical capacity, ultimately resulting in better health-related quality of life. Physical exercise promotes an anti-inflammatory response and improves immune defense through the involvement of diverse organs . The anti-inflammatory response to exercise has also been associated with a reduced risk of developing comorbidities (such as obesity) and reduced cardiovascular morbidity ,15. ThisIn this case series study, we aimed to explore the potential therapeutic role of exercise on several outcomes  in MIS-C patients. This is a case series study of a 12-wk home-based exercise intervention in children and adolescents who survived MIS-C. This study is part of a prospective cohort study aimed to explore the long-term effects of SARS-CoV-2 infection in surviving pediatric post-COVID-19 and MIS-C patients . Data from the patient’s acute phase MIS-C were retrospectively assessed through medical records. The post-infection data were collected prospectively in an outpatient clinic for COVID-19 at the Children’s and Adolescents’ Institute of the Clinical Hospital of the University of Sao Paulo between October 2020 and January 2022. Out of the 16 MIS-C patients followed at our clinic, 4 died, 3 did not meet inclusion criteria , and 3 did not accept to participate in this exercise trial. Therefore, 6 patients were included. All patients  fulfilled the MIS-C diagnosis according to the Center for Disease Control (CDC) criteria [The primary outcome was health-related quality of life, assessed by the Pediatric Outcomes Data Collection Instrument (PODCI). Secondary outcomes were CFR assessed by 13N-ammonia PET-CT imaging, cardiac function by standard echocardiography, cardiorespiratory fitness, and inflammatory and cardiac blood markers . The protocol was approved by the National and Institutional Ethical Committee of Clinical Hospital, CAAE: 37460620.8.0000.0068. Patients and guardians signed an informed consent before participants’ enrollment, and the study was conducted according to the Declaration of Helsinki. ®, Zoom®, or Google Meets® apps. The exercise intensity was assessed through the Children’s OMNI scale of perceived subject exertion (PSE) [The 12-week, 3-times-a-week, home-based exercise program used herein was thoroughly described elsewhere ,22. In bon (PSE) . Progresfmsb package  in the environment R .To assess health-related quality of life, we used PODCI, which evaluates functional health status through an 83-86 item questionnaire . This quCardiac positron emission tomography-computed tomography (PET-CT) is the gold standard noninvasive test for myocardial blood flow (MBF). The ratio of the MBF measured at maximal vasodilation over the MBF at rest is referred to as myocardial flow reserve (MFR) or coronary flow reserve (CFR), which is a measure of the vasodilatory reserve of the myocardium. Reduced CFR, in the absence of flow-limiting coronary artery disease, is believed to reflect dysfunction in the myocardial microvasculature and result in ischemia ,25. ProtCFR was calculated as the ratio of stress MBF over the rest MBF (for each left ventricle (LV) segment see , CFR at Standard transthoracic echocardiography was performed according to the recommendations of the American Society of Echocardiography and included M-mode, two-dimensional imaging, conventional, and tissue Doppler evaluation at the septal and lateral mitral annulus . The equThe z-score values for the measures were calculated according to the “Boston Children’s Hospital z-score system” . LV massThe main principle of 2DST is that each segment of myocardial tissue displays a specific pattern of gray values in the ultrasound image, commonly referred to as a speckle pattern. Tracking this acoustic pattern during the cardiac cycle enables the observer to follow the myocardial motion and to directly assess ventricular deformation . To eval2VAT) (mL/kg/min) and VO2peak (mL/kg/min). Twelve-lead ECG and gas exchange measurements were recorded continuously. Peak VO2 was determined as the mean value of VO2 during the final 30 s of the graded exercise test. The following variables were obtained breath-by-breath and expressed as 30 s averages: pulmonary oxygen uptake ; pulmonary ventilation ; end-tidal carbon dioxide pressure , ventilatory equivalent ratio for carbon dioxide (VE/VCO2), and ventilatory equivalent ratio for oxygen (VE/VO2).A symptom-limited maximal cardiopulmonary exercise test was carried out on treadmill. CPETs were performed on a treadmill with an intensity-graded, maximal effort protocol and continuous gas exchange . All tests in this study were performed by the same intrahospital laboratory at controlled room temperature with individuals in an upright position (20–23 °C). Test termination was determined by volitional exhaustion, and maximal effort was confirmed by a peak respiratory exchange ratio > 1.10, maximal heart rate > 95% age/gender-predicted values, or maximum rating of perceived exertion (RPE) . The out2peak), oxygen consumption at the ventilatory anaerobic threshold (VO2VAT), VE/VCO2 slope, the lowest VE/VCO2 and respiratory exchange ratio (RER), chronotropic reserve (CR) and heart rate peak (HRP) were analyzed as previously described [Other CPET variables such as the peak oxygen consumption . Fisher’s exact test was used to compare the frequency of coronary flow reserve , as seen in p = 0.0222 . In addition, the chronotropic reserve reduced −15% and HRP −6%  and reduced LVEF (54%), and the speckle tracking exam showed reduced GLS (−17.4%). Despite after exercise, the standard echocardiography showed normal values for cardiac function, including GLS% , the spe HRP −6% . Nonethep = 0.0202), 6/20 borderline (p = 0.0202), and 8/20 within normal values (p = 0.0001) (2peak) reduced by 18% and 19% throughout the follow-up period. Cardiac function and laboratory markers remained within normal values  . Additiol values .p = 0.0915), whereas normal values reduced from 18/20 to 13/20 (p = 0.1274). Time to exhaustion and VO2peak values improved by 8% and 15%, respectively. Cardiac function and laboratory markers remained in the normal range.Patient V is an 11-year-old male with type I diabetes who presented with fever, conjunctivitis, hypotension, shock, and abdominal pain. He needed ICU admission and respiratory support, and echocardiography abnormalities were detected at the acute phase . At the p = 0.0033), borderline significantly increased from 9/20 to 12/20 (p = 0.0012), and normal values were reduced from 11/20 to 0/20 (p = 0.0001). Cardiorespiratory fitness and laboratory markers remained unchanged. Patient VI is an 11-year-old male who presented with fever, conjunctivitis, arterial hypotension, shock, abdominal pain, and diarrhea. He needed ICU admission and respiratory and oxygen support, but no echocardiography abnormalities were seen in the acute phase . At baseTo our knowledge, this was the first study to demonstrate the effects of an exercise training program on health-related quality of life, microvascular and cardiac function, cardiorespiratory fitness, and inflammatory and cardiac blood markers in MIS-C survivors. To date, our findings suggest that exercise may positively impact the health-related quality of life, coronary flow reserve, cardiac function, and aerobic conditioning. Pediatric-COVID patients have shown reduced health-related quality of life and at least one symptom related to long-COVID 4 months after hospital discharge . MoreoveOverall, patients assessed herein, particularly those included in the exercised group, showed poor health-related quality of life. However, exercise training programs lead to an improvement in these parameters for all patients, indicating a key role of exercise in the management of MIS-C patients. Moreover, patients who followed the standard of care did not have low quality-of-life scores in the initial assessment, preventing significant improvements in the domains assessed through the PODCI.Cardiovascular complications arising from acute COVID-19 have been shown in the literature , inclusiSome studies have reported impaired microvasculature in COVID-19 and MIS-C patients . The mecBlomster et al. analyzed the correlation between CFR, exercise capacity, and cardiac systolic and diastolic function in 400 adult patients with coronary artery disease (CAD). The authors showed that maximal exercise capacity is dependent on coronary CFR in non-obstructive CAD, emphasizing the significance of microvascular circulation on cardiac performance .The abnormal CFR detected by PET-CT in our surviving MIS-C patients (PIII and PVI), mirrored by segmental peak systolic longitudinal strain reduction, seems to indicate residual damage in the coronary microcirculation as a consequence of infection. Importantly, microcirculatory impairment  was detected at the standard echocardiography even in the absence of coronary artery aneurysm. 13N PET-CT-measured impaired vasodilation capacity is associated with the increased risk of progression of congestive heart failure and mortality in adults with idiopathic cardiomyopathy . TherefoThe strengths of this study involved the investigation of patients with a rare condition and the use of gold standard methods to assess cardiac-and fitness outcomes, as well as the implementation of a newly developed home-based exercise training program aimed at treating MIS-C patients. The main limitations included the low number of patients enrolled (owing to the rarity of the condition) and the lack of a control group without MIS-C, which hampers establishing causation and limits possible insights on the natural course of the syndrome. To conclude, our results may suggest that exercise could be a useful tool in the management of MIS-C patients. Randomized controlled studies are needed to confirm or refute these exploratory findings.


Copeptin level was an excellent predictor of outcomes, with an area under the curve of 0.861 , a sensitivity of 86%, and a specificity of 60% for copeptin level of 25 pg/mL. This predictive value was superior in patients with dilated and restrictive cardiomyopathies (0.97 (CI 0.927–1.036), p < 0.0001, n = 21) than in those with hypertrophic and LV non-compaction cardiomyopathies (0.60 (CI 0.04–1.16), p = 0.7, n = 21).In children with cardiomyopathy, the severity of heart failure (HF) varies. However, copeptin, which is a biomarker of neurohormonal adaptation in heart failure, has not been studied in these patients. In this study, we evaluated the correlation of copeptin level with functional HF grading, B-type natriuretic peptide (BNP), and echocardiography variables in children with cardiomyopathy. Furthermore, we determined if copeptin levels are associated with adverse outcomes, including cardiac arrest, mechanical circulatory support, heart transplant, or death. In forty-two children with cardiomyopathy with a median (IQR) age of 13.1 years (2.5–17.2) and a median follow-up of 2.5 years (2.2–2.7), seven (16.7%) children had at least one adverse outcome. Copeptin levels were highest in the patients with adverse outcomes, followed by the patients without adverse outcomes, and then the healthy children. The copeptin levels in patients showed a strong correlation with their functional HF grading, BNP level, and left ventricular ejection fraction (LVEF). Patients with copeptin levels higher than the median value of 25 pg/mL had a higher likelihood of experiencing adverse outcomes, as revealed by Kaplan–Meier survival analysis ( Heart failure in children is associated with significant morbidity and mortality ,2. CardiIn addition to cardiomyopathies, heart failure in children can be caused by various diseases, including congenital structural heart defects, arrhythmias, toxins, and non-cardiac etiologies like sepsis ,5. WhileNeurohormonal activation plays a pivotal role in the progression of heart failure, and it also correlates with the severity of heart failure ,7,8. TheAVP is a nonapeptide secreted by supraoptic and paraventricular nuclei in the hypothalamus ,16. It iCurrently, AVP measurement has been limited in the experimental laboratory. AVP is an unstable molecule, predominantly bound to platelets and rapidly cleared due to its short half-life. Due to these characteristics, it cannot be measured by routine sandwich assays ,19. CopeSeveral adult studies in patients with heart failure have shown that copeptin can be a useful prognostic biomarker for acute and chronic heart failure ,21,22,23In this single-center prospective cohort study, we enrolled children with cardiomyopathy in different stages of heart failure aged 1 month to 18 years at the Outpatient Heart Failure Clinic, Inpatient Wards, and Intensive Care Units of Le Bonheur Children’s Hospital, Memphis, Tennessee. We included children with underlying cardiomyopathy in whom the treating cardiologists diagnosed heart failure. We excluded children if they met any of the following exclusion criteria: age less than 1 month and more than 18 years, presence of acute renal injury (serum creatinine > 1.5 mg/dL), or presence of acute liver injury (Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) > 500 IU/dL). Healthy children were enrolled in the General Pediatric Outpatient Clinic of Le Bonheur Children’s Hospital. Informed consent was obtained from parents or legal guardians as per the University of Health Science Center (UTHSC) Institutional Review Board guidelines before the study enrollment.We collected relevant demographic information, including age, gender, etiology of heart failure, medications , respiratory support , and mechanical circulatory support (ECMO and VAD). The cases were assigned the functional heart failure grading based on either Ross heart failure grading (for children aged ≤5 years) or New York Heart Association (NYHA) heart failure grading (for children aged >5 years) by the treating cardiologists specialized in pediatric heart failure at the time of enrollment . The trep = 0.05 was used. Analyses were conducted using SPSS 24 .The study aimed to identify a 25% difference in copeptin levels between the cardiomyopathy and control groups. To achieve this, a sample size of 30 participants was chosen for each group, with a statistical power of 80% and an alpha of 0.05. Continuous variables were reported as medians and interquartile ranges (IQR), while categorical variables were summarized as frequency counts and percentages. A Wilcoxon signed-rank test was applied to compare the cases and the controls. Mann–Whitney U tests or Fisher’s exact tests were applied to compare the cases with and without adverse events. Spearman’s correlation coefficients were obtained to determine the correlation between copeptin level and established measures of the severity of heart failure. Receiver operator characteristics curves analyses were performed to determine the predictability of the composite adverse outcome by copeptin level, BNP level, and LVEDD. Kaplan–Meier survival curves were derived for the composite adverse outcomes among the cohort based on the median copeptin level in the cases. A significance level of We enrolled 42 children with cardiomyopathy at different heart failure stages. p = 0.045) and healthy children (6.2 pg/mL (5.8–6.7), p < 0.001), as shown in p < 0.001) and BNP level , as presented in p < 0.001), LVEF , and serum sodium level . However, no correlation was found between copeptin levels and patients’ age  and serum osmolarity , as presented in Children with cardiomyopathy who experienced adverse outcomes had higher copeptin levels (median (Interquartile Range (IQR)) of 741.8 pg/mL (351–9.14.1) compared to those without adverse outcomes (21 pg/mL (11.9–74.4), p-value of 0.019.Univariate logistics regression analysis revealed that several factors, including copeptin level, functional HF grading, BNP level, LVEF, and LA volume, were associated with adverse outcomes. These findings are presented in p-value of 0.002 for all cases with a sensitivity of 86% and specificity of 60% for copeptin level of 25 pg/mL or higher. Copeptin levels had an even better predictive value (AUC 0.97 (95% CI 0.9–1.03), p-value < 0.001) in cases with either dilated and restrictive cardiomyopathy, but no predictive value in cases with either hypertrophic or LV non-compaction cardiomyopathy (AUC 0.61 (95% CI 0.05–1.17), p-value = 0.71). The predictive value of BNP level was similar to copeptin level in all cases, cases with dilated and restrictive cardiomyopathies, and cases with hypertrophic and LV non-compaction cardiomyopathies. Only LVEF had a predictive value in those with either hypertrophic or LV non-compaction cardiomyopathy. Lastly, we performed Kaplan–Meier survival time to event analysis using the median copeptin level of 25 pg/mL for all cases as the grouping variable. The log-Rank test showed a higher likelihood of adverse events in cases with copeptin levels higher than the median value during the follow-up period, as illustrated in The receiver operator characteristics (ROC) curves were obtained to assess predictive values of copeptin level, BNP level, LVEF, and LA volume for all cases, cases with dilated and restrictive cardiomyopathies, and cases with hypertrophic and LV non-compaction cardiomyopathies, as illustrated in In this study of children with different types of cardiomyopathies, we found elevated copeptin levels are associated with worse outcomes in children with cardiomyopathy. This association was significant even after adjusting for the severity of their heart failure. Copeptin levels were found to be a moderately to highly accurate predictor of adverse outcomes in children with cardiomyopathy, with a sensitivity of 86% and specificity of 60% for levels of 25 pg/mL or higher. However, this accuracy was only observed in cases of dilated and restrictive cardiomyopathy, with no predictive value for hypertrophic and LV non-compaction cardiomyopathy. BNP levels were similarly predictive across all types of cardiomyopathies when compared to Copeptin levels. Interestingly, only LVEF was found to be a predictor in cases of hypertrophic and LV non-compaction cardiomyopathy. Overall, these results suggest that copeptin levels may be a useful tool for predicting outcomes in children with certain types of cardiomyopathies. We found that most patients in our group who had end-stage heart failure and were waiting for a heart transplant were in the dilated and restrictive cardiomyopathy group. These patients had severe systolic and diastolic function and were receiving inotropic support. We considered the severity of their heart failure when analyzing the data, but it still might have an impact on the results. This may be why copeptin was a better predictor of adverse outcomes in these patients. Interestingly, copeptin levels were not a reliable predictor in hypertrophic and LV non-compaction cases, which warrants further investigation. Our study sheds light on an area that has not been well explored before, and we recommend conducting a larger multicenter study with comparable heart failure severity in different types of pediatric cardiomyopathies subgroups to further our understanding.Copeptin is a larger molecular fragment of pre-pro vasopressin (a precursor molecule for AVP and copeptin) secreted in equimolar amounts to Arginine vasopressin (AVP) secreted by hypothalamus neurally transported to the posterior pituitary and released in the bloodstream ,19. ExceSeveral studies have shown that copeptin levels can predict outcomes in adults with heart failure ,21,22,23Pediatric data on copeptin level as a predictor of adverse outcomes are limited to few studies, including arterial hypotension in critically ill children, pulmonary hypertension, ventricular dysfunction with vaso-occlusive crises of sickle cell anemia, and pediatric acute heart failure ,31,32,33It is important to note that our study has certain limitations. Due to a small sample size and diverse patient characteristics, our findings may not apply to a larger population. We could not establish a temporal relationship between copeptin level and heart failure progression due to the lack of serial measurements. Furthermore, we could not consider many confounding factors, including different heart failure treatments, which may have affected our results. However, this is the first study to compare the predictive value of copeptin levels in a cohort of children with cardiomyopathy. Our study provides valuable information to help design future large multi-centered studies.Copeptin levels are associated with the severity of heart failure and adverse outcomes in children with cardiomyopathy. Copeptin levels are moderately to highly accurate predictors of adverse outcomes in children with cardiomyopathy. However, this accuracy was only observed in dilated and restrictive cardiomyopathy cases, with limited predictive value for hypertrophic and left ventricular non-compaction cardiomyopathy. BNP levels are similarly predictive across all types of cardiomyopathies. The clinical usefulness of copeptin as a biomarker beyond BNP levels in children with cardiomyopathy needs further investigation.


Fatigue is one of the most commonly reported symptoms after subarachnoid hemorrhage (SAH) and is indirectly associated with physical activity (PA). Associations between fatigue and PA are primarily examined based on conventional measures (i.e. a single fatigue score or average PA levels), thereby assuming that fatigue and PA do not fluctuate over time. However, levels of fatigue and PA may not be stable and may interrelate dynamically in daily life. Insight in direct relationships between fatigue and PA in daily life, could add to the development of personalized rehabilitation strategies. Therefore we aimed to examine bidirectional relationships between momentary fatigue and PA in people with SAH.People (n = 38) with SAH who suffer from chronic fatigue were included in an observational study using Ecological Momentary Assessment (EMA) and accelerometry. Momentary fatigue was assessed on a scale from 1 to 7 (no to extreme fatigue), assessed with 10–11 prompts per day for 7 consecutive days using EMA with a mobile phone. PA was continuously measured during this 7-day period with a thigh-worn Activ8 accelerometer and expressed as total minutes of standing, walking, running and cycling in a period of 45 min before and after a momentary fatigue prompt. Multilevel mixed model analyses including random effects were conducted.Mean age was 53.2 years (SD = 13.4), 58% female, and mean time post SAH onset was 9.5 months (SD = 2.1). Multilevel analyses with only time effects to predict fatigue and PA revealed that fatigue significantly (p < 0.001) increased over the day and PA significantly (p < 0.001) decreased. In addition, more PA was significantly associated with higher subsequent fatigue  and higher fatigue was significantly associated with less subsequent PA . Moreover, these associations significantly differed between participants (p < 0.001).By combining EMA measures of fatigue with accelerometer-based PA we found that fatigue and PA are bidirectionally associated. In addition, these associations differ among participants. Given these different bidirectional associations, rehabilitation aimed at reducing fatigue should comprise personalized strategies to improve both fatigue and PA simultaneously, for example by combining exercise therapy with cognitive behavioral and/or energy management therapy.The online version contains supplementary material available at 10.1186/s12984-023-01241-5. About 30–90% of people with subarachnoid hemorrhage (SAH) suffer from chronic fatigue, –4 which Associations between fatigue and PA after stroke are primarily assessed in studies with a cross-sectional design . ConsequIn a study that combined EMA data on fatigue (assessed 10 times a day) and diary-based PA scores, people with stroke reported higher fatigue levels when they reported more PA before the fatigue prompt and when they perceived activities as more effortful. In addition to this overall effect, interindividual differences were found in the increase in fatigue with more effortful daily activities . In patiInsight in real-life momentary relationships between fatigue and PA in people with SAH is lacking, but could add to the development of personalized rehabilitation programs ultimately increasing the effectiveness of interventions aimed at fatigue. For example, if people with SAH instantly reduce their PA in response to fatigue, rehabilitation aimed at coping with fatigue might help them to continue their activities despite their fatigue, or for people who experience more fatigue in the afternoon, rehabilitation in the morning might be more effective. Therefore, the aim of this study was to examine bidirectional relationships between momentary fatigue and device based assessed PA in people with SAH. We hypothesized that more PA is followed by higher subsequent fatigue and that higher fatigue predicts less subsequent PA.Consecutive patients with SAH, who were treated at Erasmus MC University Medical Centre Rotterdam (Augustus 2017-May 2019) and patients treated at Elisabeth-TweeSteden Hospital (January 2019-January 2020) were screened for eligibility. Inclusion criteria were: at least 18 years of age, 3 to 12 months post SAH onset, living at home and experiencing fatigue since SAH . Exclusion criteria were: previous stroke or suffering from another severe chronic and/or neurological disease, other clinical reason for fatigue, insufficient mastery of the Dutch language and inability to fill in the electronic diary. After inclusion a researcher visited the participants at home, where a semi-structured interview was conducted to assess baseline characteristics  and participants received instructions for filling in the electronic diary and wearing the accelerometer. Participants wore the accelerometer for 7 consecutive days and they filled in the electronic diary during the same days. For descriptive purposes, before the home-visit participants were asked to fill in the fatigue severity scale (FSS) questionnaire. All participants provided written informed consent before inclusion. The medical ethics committee of Erasmus MC (MEC-2017-523) approved the study.Momentary fatigue was assessed with an electronic diary using the MovisensXS application on a mobile phone (Alcatel U3), that participants received the day before the measurement week. Patients were asked 10–11 times per day “How fatigued do you feel at this moment?”  to 7 (extremely fatigued), which corresponds with the scale of the FSS questionnaire . ParticiPA was assessed with the Activ8 accelerometer , which is a small (30 × 32 × 10 mm) and light-weighted (20 g) device that was attached on the front of the upper thigh with Tegaderm™ skin tape. The Activ8 is validated  and founThe Activ8 has a tri-axial accelerometer which detects 6 postures or movements: lying, sitting, standing, walking, cycling, running. PA was defined as the combined category of standing, walking, running and cycling. Data was continuously collected for 24 h/day during 7 consecutive days and summarized and stored in 30 s epochs. In this study only waking time was considered. Total time in minutes of PA in a period of 45 min prior and after a fatigue prompt was calculated. A time interval of 45 min was chosen since this was the minimum time period between two fatigue prompts and in this way we were able to make maximum use of the Activ8 data.For descriptive purposes, trait fatigue was assessed with the validated and widely used Fatigue Severity Scale (FSS) , 30. TheRStudio Version 1.4.1103 was used for all statistical analyses. Descriptive statistics were used to check statistical assumptions. Baseline characteristics of the participants and descriptive statistics of fatigue and PA were described by mean values and standard deviations for variables on an interval scale or frequencies and percentages for categorical variables. If participants showed less than 30% EMA compliance, data were not valid based on EMA guidelines and excluded from the analyses. In addition, irrespective of number of waking hours, if Activ8 data was not representative based on the paper diary of the participants, that day was excluded from the analyses. Periods of non-wear as indicated by the participants in the paper diary were also excluded.2 as covariates. Time2 effects were included to take into account possible non-linear effects of time on fatigue and PA over the day, if that improved model fit. In addition, we examined whether random slopes for time significantly contributed to the model fit. Subsequently, we examined univariable associations between baseline characteristics and fatigue and PA, by conducting separate models with fatigue or PA as dependent variable and the given characteristic and time effects as covariates.We conducted multilevel-mixed models with repeated measurements of fatigue and PA (level-1) nested within participants (level-2). First, we examined the course of fatigue and PA over the day by conducting two models with either fatigue or PA as dependent variable and time and timebefore the fatigue prompt as covariate and one model with PA time in the 45 min period after the fatigue prompt as dependent variable and momentary fatigue score as covariate. The momentary covariates fatigue and PA were person-mean centered, thereby modelling the momentary change from a person’s usual fatigue / PA level. Other covariates of interest in both models were, time, time2 and day type (week day or weekend day). The models were adjusted for sex, age and the baseline characteristics that were significant (p < 0.05) in the univariable models. For each of the models we examined whether interactions of either fatigue or PA with time significantly contributed to the model fit based on the Bayesian Information Criteria. Also, we examined whether interactions of fatigue or PA with the characteristic(s) that were significantly associated with fatigue or PA in the univariable models significantly contributed to the model fit. We added random intercepts and slopes for time and either PA time or fatigue and a continuous time auto-regressive correlation structure to the model, to account for the correlations in the data. Model assumptions, , were met. The two final models are presented in Additional file 1.Finally, to examine bidirectional associations between fatigue and PA, two multivariable models were built: one model with fatigue as dependent variable and PA time in the 45 min period In total, 42 patients participated in the study. One patient did not reach minimal EMA compliance of 30% and was therefore excluded from the analyses. In addition, Activ8 data of 3 participants were missing, one Activ8 was damaged and two were lost, resulting in a total group of 38 participants for the analyses, with a mean age of 53.2 years SD = 13.4) and 9.5 months (SD = 2.1) post SAH onset. Mean FSS score of the group was 5.11 (SD = 1.18) and 31 patients (82%) were fatigued based on the cut-off score of 4. Baseline characteristics of all participants are presented in Table 3.4 and 92; β=-0.007, p < 0.001) and that this course significantly differed among participants . In univariable analyses we found that smokers had significantly higher momentary fatigue than non-smokers  and that momentary fatigue was significantly higher on week days than in the weekend . For all other baseline characteristics no significant associations with momentary fatigue were found.Mean momentary fatigue of the total group was 3.22 SD = 1.46). Mean momentary fatigue at the first prompt, at 09:36 AM (SD = 21 min), was 2.51 (SD = 1.16) and at the last prompt, at 08:40 PM (SD = 17 min), was 3.76 (SD = 1.55). The left panel of Fig. .46. Meanbefore the fatigue prompt was 15.41 (SD = 13.3) minutes (34.2%) and in the 45 min after the fatigue prompt 14.96 (SD = 13.0) minutes (33.2%). In the right panel of Fig. after the fatigue prompts over the day for all participants separately and for the whole group (bold line) are presented. Mean PA time in the 45 min after the first fatigue prompt, at 09:36 AM (SD = 21 min), was 18.16 (SD = 13.1). Mean PA time in the 45 min after the last fatigue prompt, at 8:40 PM (SD = 17 min), was 8.08 (SD = 9.1) minutes. PA time in the 45 min after the fatigue prompt slightly increased at the start of the day  and subsequently decreased over the day  and this course significantly differed among participants . Univariable analyses showed that longer stay at the hospital (β=-0.24), poor WFNS score  and neurosurgical treatment (β=-4.74) were significantly (p < 0.05) associated with less PA. For all other baseline characteristics no significant associations with PA were found.Of all 266 measurement days, 5 days 1.9%) were considered as non-representative based on the notes of the participants in the paper diary. Mean PA of the total group per day was almost 5 h , which is 32.6% of the mean total analyzed time per day of 15.2 h (SD = 1.0) . Mean PA time in the 45 min .9% were 2, age, sex, type of day, duration of hospital stay, WFNS score and smoking status. In addition, the change in fatigue after more PA differed among participants . Fatigue was significantly higher on week days than on weekend days . The other covariates in the model  were not independently associated with fatigue. The interaction effects of PA with the time variables and with day type and smoking status did not significantly improve the model fit.The details of the multivariable model with fatigue as outcome variable are presented in Table 2, age, sex, type of day, duration of hospital stay, WFNS score and smoking status. In addition, the change in PA after higher fatigue levels differed among participants . Both poor WFNS score  and being a smoker  were associated with lower PA. The other covariates in the model  were not independently associated with PA. The interaction effects of fatigue with the time variables and with duration of hospital stay and WFNS category did not significantly improve the model fit.The details of the multivariable model with PA as outcome variable are presented in Table By combining prospective EMA measures of fatigue and accelerometer-based PA in daily life, we found direct relationships between fatigue and PA in people with SAH, thereby adding new insights to existing literature on cross-sectional associations between trait fatigue and mean PA levels , 13, 18.When we compare our findings to EMA literature on the relationships between fatigue and PA, similarities and differences can be noticed. For example, our findings on the positive relationship between PA and subsequent fatigue are in line with results from an EMA study in people with stroke that showed that more PA was followed by higher fatigue . In peopContrary to what has been found in healthy people , we founBesides physiological mechanisms as described in the previous paragraph, psychological mechanisms may also play a role in the interplay between fatigue and PA in daily life. People with SAH might avoid PA due to fear of worsening their fatigue or recurrence of SAH or because they believe that fatigue diminishes after resting , 38, whiThe bidirectional interplay between fatigue and PA in daily life found in this study highlights the importance of developing rehabilitation strategies simultaneously targeting fatigue and PA to eventually reduce fatigue. Behavioral interventions addressing aspects as energy management and activity pacing strategies seem important to balance PA and fatigue levels. In addition, cognitive interventions targeting coping with fatigue, self-efficacy and kinesiophobia (e.g. by providing information about SAH and the chances of recurrence of SAH) seem useful to prevent avoidance behavior and increase the likelihood of performing PA despite experiencing fatigue . Such a This study has some limitations that need to be considered. First of all, PA before and after a fatigue prompt of people with SAH in our study was rather low. In future studies, it would be interesting to study the relationship between fatigue and PA using activity-based EMA prompts. Participants are then prompted after a given amount of minutes of PA or no PA. This will increase the insight in the effect of longer bouts of PA on fatigue. In addition, the sample size of our study was relatively small, however, given the many repeated measurements within persons, this sample size was considered appropriate for modelling associations between PA and fatigue . In addiIn conclusion, by combining EMA measures of fatigue with accelerometer-based PA we found that momentary fatigue and PA are bidirectionally associated in people with SAH. People with SAH reduced their PA in response to fatigue and more than usual PA resulted in higher levels of fatigue. In addition, the relationships between fatigue and PA differed among participants. Given the dynamic interplay between fatigue and PA in daily life and the differences between participants in this interplay, these findings should be taken into account in developing personalized rehabilitation programs aimed at reducing fatigue and enhancing PA after subarachnoid hemorrhage.Below is the link to the electronic supplementary material.Additional file Additional file 1: Final models analysis (DOCX)


P for age = 0.25 between sexes). Women had smaller absolute LV volume and mass than men across the spectrum of regurgitation volume (RVol) (P ≤ 0.01). In patients with ≥ moderate AR and with adjustment for body surface area, indexed LV end-diastolic volume and mass were not significantly different between sexes  but men had larger indexed LV end systolic volume and lower LV ejection fraction (P ≥ 0.01). Women were more likely to have NYHA class II or greater symptoms than men but underwent surgery at a similar rate. Prevalence and extent of LGE was not significantly different between sexes or across RVol. Increasing RVol was independently associated with increasing ECV in women, but not in men (adjusted P for interaction = 0.03). In conclusion, women had lower LV volumes and mass than men across AR severity  but their ECV increased with higher regurgitant volume, while ECV did not change in men. Indexing to body surface area did not fully correct for the cardiac remodeling differences between men and women. Women were more likely to have symptoms but underwent surgery at a similar rate to men. Further research is needed to determine if differences in ECV would translate to differences in the course of AR and outcomes.Whether sex differences exist in the cardiac remodeling related to aortic regurgitation (AR) is unclear. Cardiac magnetic resonance (CMR) is the current non-invasive reference standard for cardiac remodeling assessment and can evaluate tissue characteristics. This prospective cohort included patients with AR undergoing CMR between 2011 and 2020. We excluded patients with confounding causes of remodeling. We quantified left ventricular (LV) volume, mass, AR severity, replacement fibrosis by late Gadolinium enhancement (LGE), and extracellular expansion by extracellular volume fraction (ECV). We studied 280 patients (109 women), median age 59.5  years ( The natural history of AR has been characterized by progressive LV dilatation and hypertrophy in response to the hemodynamic load on the ventricle, with increased wall stress and eventual manifest LV dysfunction6. Myocardial remodeling varies significantly among individuals with different forms of VHD, and includes adaptive and maladaptive changes in ventricular shape, volume, cellular, and extracellular components7.Aortic regurgitation (AR) is a common form of valvular heart disease (VHD) characterized by volume and pressure overload of the left ventricle (LV)8. In a recent study, ECV measured by CMR was strongly correlated with interstitial fibrosis measured on histology at the time of surgery in patients with severe AR9.Cardiac magnetic resonance (CMR) is an accurate and reproducible non-invasive method to assess ventricular volumes, mass, and tissue characteristics. In addition to a direct and accurate assessment of aortic regurgitant volume (RVol), CMR can assess myocardial replacement fibrosis  and interstitial expansion . Myocardial fibrosis in AR has been described in histopathology studies and was characterized by increased fibronectin and non-collagen components12 and primary mitral regurgitation13. However, there is less clarity on the sex differences in the adaptive response to AR14 and particularly fibrosis burden. The aim of this study was to assess if there are sex differences in myocardial remodeling and fibrosis in patients with isolated AR.Important sex differences in myocardial remodeling have been described in aortic stenosis (AS)clinical history: (1) obstructive coronary artery disease (CAD), history of myocardial infarction, or coronary revascularization; (2) cardiomyopathy deemed unrelated to AR ; or (3) prior cardiac surgery or transcatheter structural intervention. To avoid ambiguity regarding confounding etiologies of any LV fibrosis detected, we further excluded patients with the following findings on CMR: congenital heart disease and aortic coarctation, coexisting other valvular disease including AS that was greater than mild in severity , except secondary tricuspid regurgitation deemed related to AR. We also excluded patients with cardiac devices where susceptibility artifacts limit accurate T1 mapping19.Patients undergoing a contrast CMR at Houston Methodist Hospital  were enrolled into a prospective observational CMR registry . We included patients with AR enrolled between July 2011 and March 2020. The determination of AR presence and its severity was done according to the CMR results. No patients with acute AR  were included. Patients enrolled in the registry undergo a thorough baseline patient interview and review of medical records at the time of imaging. Patients were excluded if they had any confounding causes of LV fibrosis by The patient enrollment process is summarized in Fig. 19.CMR images were acquired using either 1.5- or 3.0-T clinical scanners  with phased-array coil systems. CMR examinations began with cine-CMR for anatomic and functional assessment in a short-axis stack, and standard 2-, 3-, and 4-chamber views using a steady-state free-precession (SSFP) sequence with typical flip angle of 65° to 85°; repetition time (TR) of 3.0 ms; echo time (TE) of 1.3 ms; in-plane spatial resolution of 1.7 to 2.0 mm × 1.4 to 1.6 mm; slice thickness of 6 mm, with 4 mm interslice gap; and temporal resolution of 35–40 ms. Anatomic assessment of the aortic valve was performed with the use of cine SSFP sequences. The 3-chamber view and coronal LV outflow views were used to prescribe a parallel series of at least 3 thin (4–5 mm) slices in short axis to provide assessment of the aortic valve’s morphology. Phase contrast CMR was performed at the level of the ascending aorta, sinotubular junction, left ventricular outflow tract (LVOT) and the pulmonary artery. The typical parameters were flip angle of 25°–30°, TR ~ 5 ms, TE of 2.4 ms, reconstructed in-plane spatial resolution of ~ 2.0 × 2.4 mm, slice thickness of 6 mm, and temporal resolution of ~ 40–50 ms. The initial velocity encoding used was 150 cm/s for at the LVOT and pulmonary artery, and 250 cm/s at the sinotubular junction. Adjustments were made according to the peak velocity across the aortic valve20.LGE imaging was performed using a magnitude and phase-sensitive segmented inversion-recovery sequence, approximately 10 min after intravenous gadolinium contrast administration . Parameters were in-plane spatial resolution of 1.8 × 1.3 mm and slice thickness of 6 mm, with inversion time adjusted to null normal viable myocardium. Cine- and LGE-CMR images were obtained in matching short- and long-axis planes to cover the entire ventricle20.The ECG triggered modified Look Locker inversion recovery (MOLLI) sequence was used for assessment of myocardial T1 relaxation times in a mid-ventricular slice in all patients. Native myocardial T1 relaxation time was measured before administration of contrast. Acquisition scans for post contrast T1 mapping were performed after the standard delayed enhancement acquisition protocol for a mid- ventricular matching slice, approximately 15–20 min after the infusion of the contrast agent. Parameters for MOLLI technique include slice thickness of 6 mm, voxel size 2.1 × 1.6 × 6 mm, TE = 1.09, TR = 675, flip angle = 35°, twofold parallel imaging. Precontrast 5(3)3 and post-contrast 4(1)3(1)2 heart beat sampling schemes were used on the 1.5-Tesla scanner and pre-contrast 5(4)2 and post-contrast 4(1)2(2)2 heart beat sampling schemes on the 3.0-Tesla scanner. Shimming and delta frequency adjustments were applied to minimize off-resonance artifacts21.Ventricular volumes were measured by planimetry of the endocardial borders, on a stack of short-axis images acquired from cine-CMR covering both ventricles from base to apex. Papillary muscles and trabeculae were excluded from blood volume. LV end-diastolic volume (EDV), LV end-systolic volume (ESV), right ventricular (RV) EDV, and RV ESV were calculated by summation of these images. The stroke volume for each ventricle was determined by subtracting the ESV from the EDV. The LVEF and RVEF were calculated by dividing the stroke volume by the EDV of the respective ventricle. LV mass was calculated by tracing LV epicardial and endocardial borders at end diastole and assuming myocardial density of 1.05 g/ml. Papillary muscles and trabeculations were included in LV mass. Left ventricular dilatation and hypertrophy were defined as an indexed LVEDV and LV mass > 95th percentile of the normal range, according to age and sex22.The presence and extent of LGE was assessed in all LV segments according to the American College of Cardiology/American Heart Association 17-myocardial-segment model by a consensus of 2 readers who were blinded to clinical history and other imaging information. To mitigate the effect of imaging artifacts, replacement fibrosis was only considered present if it was visually identified on 2 contiguous or orthogonal slices and seen on both magnitude and phase-sensitive image reconstructionWe used the full width half maximum method to quantify the extent of LGE. The RVol was calculated using the direct method from phase contrast imaging at the level of the sinotubular junction or via the difference between LV outflow tract forward flow and net pulmonary artery flow. The regurgitant fraction was calculated as (reverse volume/forward volume * 100%). Analysis of LV volume, mass, AR severity, and LGE extent was performed on Precession (Heart Imaging Technologies).Analysis of T1 values was performed using manually contoured regions of interest, for both pre and post contrast midventricular slices. Extracellular volume (ECV) was calculated as: ECV = ∆R1 myocardium/∆R1 blood × (100 − hematocrit), where ∆R1 myocardium or change in relaxation rate is given by: 1/T1 myocardium post contrast injection − 1/T1 myocardium pre-contrast injection, and ΔR1 blood = 1/T1 blood-post contrast − 1/T1 blood-pre-contrast administration. Hematocrit was measured on a venous blood sample obtained at the time of CMR. By this technique an estimate of T1 is encoded in the intensity of each pixel. ECV, T1 pre-contrast and T1 post contrast values were calculated separately for each of the six segments in the midventricular slice before and after contrast administration. We applied the ECV analysis to the six segments at the mid-ventricular level. Measurements were calculated as an average of all segments after censoring segments with LGE or artifact (only 6 segments had artifacts). An offset of 20% from epicardial and endocardial contours was applied to the T1 sequences to reduce bias from partial volume effects.24.CMR42 Version 5.6  was used for ECV analysisClinical follow-up was initiated from the time of CMR imaging. Event data and last follow up date were gathered from medical record review, telephone interviews with the patients, relatives, or their health care providers. Management plans including surgery vs medical therapy was ascertained.P value of < 0.05 was considered statistically significant.Distribution of continuous variables was tested by The Kolmogorov–Smirnov test. Data was presented as frequencies and percentages for categorical variables and as mean  or median  for continuous variables. Comparisons between groups were conducted using the Student’s t tests or Mann Whitney U tests for continuous variables and chi-square or Fisher exact tests for categorical variables as appropriate. The differences in ventricular volume, mass, and ejection fraction between men and women according to RVol were evaluated by the generalized linear models (GLM). Subgroup analysis was done in patients with RVol > 30 ml. Factors associated with ECV fraction were determined by the multivariable GLM. Variable selection for the multivariable model was conducted based on the clinical importance and also using the Stata’s Lasso technique with the cross-validation selection option. The interaction between sex and RVol in the association with ECV fraction was evaluated using the spline interpolation and also in the GLM model. The analyses were performed on SPSS version 21  and Stata version 16.1 . A P = 0.25. The prevalence of hypertension was similar between sexes  as was the systolic blood pressure (P = 0.84). Women had a slightly lower diastolic blood pressure than men (P = 0.01). Men and women had a similar prevalence of diabetes  and hyperlipidemia . There were 24/280 (8.5%) of patients with mild AS and the remainder had no AS. No significant difference in the prevalence of AS was found between men and women (P = 0.66).Patient characteristics are presented in Table P = 0.006). Women had smaller absolute LVEDV, LVESV, and mass across RVol degrees (P ≤ 0.04). Adjustment to body surface area showed an overall higher indexed LVEDV and indexed LV mass in men primarily in lower degrees of regurgitant volume. In ≥ moderate AR (RVol > 30 ml), no significant differences in indexed LVEDV and indexed LV mass between men and women were noted, but indexed LVESV was higher in men along with a lower LVEF. There was no significant interaction with sex and RVol in the association with LVEF  LGE burden was 2.55 % of the myocardium, which was not significantly different between men % and women %, P = 0.22. No statistically significant association was present between LGE burden and ECV ; or between presence of LGE and RVol (P = 0.17), including in the total population or in subgroups of men or women.LGE was present in 46 (16.4%) of patients and the prevalence was similar in men (18.7%) vs women (12.8%), P = 0.03). Diabetes was positively associated with increased ECV (P = 0.03) and no significant association between ECV and patients’ age, aortic valve leaflet morphology, hypertension, hyperlipidemia, symptoms, LV volumes, or LVEF .In the total population, the median ECV fraction was higher in women compared to men (26.4 ± 44.5% vs. 25.2 ± 44.6% P = 0.29). No statistically significant difference in ECV was seen between 1.5 Tesla and 3 Tesla scans (P = 0.42).In a group of normal volunteers scanned at our institution (n = 28), no statistically significant difference in ECV was noted in between male (median ECV 24 ± 4%) and females (median ECV 25 ± 4%) (P = 0.03). In women, increased RVol was positively associated with increased ECV, but not in men . Follow up on aortic valve replacement (AVR) vs medical management was available in 98 of 100 patients with ≥ moderate AR . Sixty patients (61.2%) underwent AVR at a median of 27  days from the CMR study date; and 38 (38.8%) were managed medically at the end of follow up. However, the rate of AVR was similar between men and women (55.6% of women vs. 62.5% of men), P = 0.58.In ≥ moderate AR, women were more likely to have symptoms  cohort35. Myocardial fibrosis in AR is thought to be related to increased fibronectin and glucosamine expression with altered collagen expression and organization34. To the best of our knowledge, no prior studies have examined sex differences in the extent of myocardial fibrosis.It has been long recognized that the pressure and volume overload exerted on the left ventricle by AR results in cellular and extracellular changes, including myocardial fibrosis36. In another study that included 9 patients with severe AR, ECV measured on 3 Tesla CMR was strongly correlated with the extent of interstitial fibrosis on histology 9. There was no significant relationship between the amount of LGE and the magnitude of fibrosis determined by histology. Conversely, in a study that included 26 severe AR patients, LGE was present in 69% of patients and the correlation between LGE and histology was good . ECV was not assessed37.The development of tissue characterization techniques by CMR has allowed for the non-invasive assessment of cardiac fibrosis and proved to be prognostically important in aortic stenosis and other disease states. A small CMR study by Sparrow et al. demonstrated that myocardial T1 mapping has the potential for showing differences between relaxation times in AR and in normal hearts38. The extent of cellular versus extracellular remodeling is another potential explanation. Women may have a greater degree of extracellular remodeling than men, leading to a higher ECV with increasing regurgitation severity, while men do not. Similar to LV cavity remodeling, this finding could also suggest that women are manifesting relatively greater degrees of interstitial fibrosis than men for the same degree of significant AR; and that AR severity thresholds may be different in men and women.It is unclear why women develop an increase in ECV with higher regurgitant volume. It is possible that AR is associated with activity of the renin–angiotensin–aldosterone system, which is implicated in cardiac fibrosis and has known sex differences in its activation in animal models of AR39, the recommendation is less likely to be uniformly followed across practices compared to thresholds of symptoms, LVEF and absolute LV end systolic diameter, which may lead to an unnecessary delay of treatment in women. This is supported by the finding of women being more likely to have symptoms than men at ≥ moderate AR but undergoing surgery at a similar rate. However, confirmation of these findings is needed considering the relatively small number of women with severe AR in our study.Our investigation highlights important differences and similarities between men and women with AR. Indexing LV volumes and mass to BSA appears to correct for the differences between men and women across patients with ≥ moderate AR. But as discussed above, indexed LV volumes and mass by CMR were larger in men than in women in MESA, suggesting women may be incurring greater increases in LV volume and mass than men do for the same degree of AR. Our study also highlights the importance of indexing LV parameters. Although indexing LV end systolic diameter to body surface area is recommended by the guidelines particularly for women and small patientsThe observation of increased ECV in women with increasing regurgitant volume needs confirmation in larger independent cohorts; in addition to longitudinal follow up to determine if an increase in ECV translates to differences in symptoms, reverse remodeling after surgery, and long-term outcomes.26. In addition, a potential selection bias in referring patients to CMR can not be excluded in our study. This may also have influenced the findings on ejection fraction and LVESV and their differences in men versus women, if the rates and timing of referral to CMR is different between men and women. We attempted to alleviate this bias by using generalized linear modeling analysis of continuous variables and controlling for confounders in ECV analysis, particularly leaflet morphology  and diabetes status. Despite this limitation, we believe it is imperative to study AR in women considering their relative under-representation in previous and current research studies of AR.The spectrum of AR severity was different between men and women, and the number of women, particularly those with severe AR was small as three out of four patients with severe AR are menNot all patients enrolled underwent specific testing to rule out other possible confounding causes of myocardial fibrosis . However, clinical history and available diagnostic testing results were thoroughly evaluated to minimize confounding factors. ECV fraction is not specific to fibrosis and is slightly higher in women compared to men in healthy adults. However, multiple studies have validated ECV against myocardial fibrosis in histologic specimens including in VHD. ECV is also positively associated with diabetes, but we controlled for the presence of diabetes in multivariable analysis and its prevalence was not different between men and women. The CMR results may influence the decision to proceed with surgery, and conclusions about the rate of surgery in men vs women should be tempered by this potential bias. Finally, we present our results according to regurgitant volume, not fraction. It could be argued that for the purposes of LV remodeling assessment, the regurgitant volume might be a better representative marker of the hemodynamic load (not necessarily outcomes); since the regurgitant fraction corrects for the smaller stroke volume in women and might obscure some sex differences in these parameters.Our study demonstrates sex differences in ventricular cavity and tissue remodeling in aortic regurgitation. Indexing ventricular parameters to body surface area does not fully resolve differences ventricular volumes between men and women, Women demonstrated an increase in ECV at higher degrees of regurgitant volume, whereas men do not. In contrast, myocardial replacement fibrosis as assessed by LGE is relatively uncommon in isolated AR and is not associated with sex or AR severity. Women were more likely to have symptoms than men at ≥ moderate AR but underwent surgery at a similar rate. Further research is required to confirm these findings and investigate their implications on development of symptoms, determining the optimal timing of surgery, reverse remodeling after surgery, and long-term outcomes.Supplementary Table 1.


Tetralogy of Fallot (ToF) is one of the most common congenital cyanotic heart lesions and can present to a variety of health care professionals, including teams working in pediatric intensive care. Pediatric intensive care teams may care for a child with ToF pre-operatively, peri-operatively, and post-operatively. Each stage of management presents its own unique challenges. In this paper we discuss the role of pediatric intensive care in each stage of management. It is tApproximately 20% of patients with ToF also have pulmonary atresia (PA) , which iThese variations in patients’ anatomy produce a continuum of physiological sequalae that pose ongoing challenges to clinicians in the management of this group pre- and post-operatively within a pediatric intensive care unit (PICU) setting.Associated chromosomal anomalies for this patient group include 22q11 microdeletion and trisomy 21, 18, and 13 , 6, withBefore considering the specific physiology and management, it is vital to ensure that children with ToF presenting acutely to any healthcare provider are resuscitated using a standard “ABCDE” approach. However, an understanding of the underlying physiological factors that are unique to ToF may influence clinicians’ decision-making, for example, in ensuring optimization of physiology prior to induction of anesthesia.Once immediate life-threatening emergencies have been managed, treatment of the specific physiological factors relating to ToF patients should be instigated. The different anatomical and physiological features for ToF are described below.This article presents a discussion of the specific pre-operative and post-operative management of this patient group requiring intensive care.2.Due to the four anatomic characteristics described above, mixing of oxygenated and deoxygenated blood between the pulmonary and systemic circulations occurs. Mixing most commonly occurs at the level of the VSD, typically with a right-to-left shunt causing systemic cyanosis . The degPre-operatively, the majority of ToF patients are well and are managed in the community under pediatric and cardiology care until they have reached a suitable weight to undergo complete surgical repair. However, a small group of neonates and infants will present with profound hypoxia or significant “spelling,” or have a lesion that is dependent on a patent ductus arteriosus (PDA) to allow adequate pulmonary blood flow.-Duct dependent circulation-Systemic vascular resistance (SVR)-Pulmonary vascular resistance (PVR)-Diastolic function-Dynamic RVOTO from sub-valvular muscle bundles (“spelling”).When dealing with these situations, the PICU team needs to consider the following factors:2.1.Neonates born with severe RVOTO, or pulmonary atresia, require a PDA to enable adequate pulmonary blood flow to allow oxygenation . ClosureStenting of the PDA or the RVOTO may be an option through cardiac catheterisation to reduce the requirement for prostaglandin, providing more secure pulmonary blood flow while awaiting primary ToF repair . AlthougIf an mBTT shunt is required, it is important to consider the potential complications when managing these patients post-operatively. The core principles of the post-operative course for mBTT shunts patients are to ensure adequate blood flow to both pulmonary and systemic circulations and to maintain shunt patency with anticoagulation.2) of between 75% and 80%.Children with pulmonary overcirculation (high pulmonary blood flow) may present with relatively high oxygen saturation, edematous lungs on chest x-ray or ultrasound, low central venous saturation, and rising lactate. Pulmonary overcirculation can be managed by manipulating pulmonary and systemic vascular resistance in order to reduce blood flow to the lung (by increasing PVR) and ensure a balanced blood flow. It may be helpful to determine the Qp:Qs ratio to assist in directing appropriate therapies, with the aim of achieving a Qp:Qs ratio of 1:1–1.5 with systemic arterial oxygen saturation  will increase right-to-left shunt by decreasing LV end-diastolic pressure (LVEDP), and therefore increase the pressure gradient between the RV and LV cavities . This caVasoconstriction (and subsequent increase in SVR) can therefore be used to reduce right-to-left shunt in extreme physiological situations . α agoni2.3.PVR is usually not a significant issue in pre-operative cases of ToF due to pulmonary circulation being protected by the RVOTO. It is more relevant in a “pink” Fallot's, with little RVOTO. However, high PVR increases the degree of right-to-left shunting by increasing the RV afterload, in addition to the RVOTO, to further reduce pulmonary blood flow. This is probably of secondary importance to SVR when dealing with profound cyanosis in ToF, but reducing PVR can help with significant spelling episodes.PVR can be reduced in order to promote pulmonary blood flow in a case of cyanotic uncorrected ToF, in parallel to increasing SVR. Management of PVR needs to be conducted in conjunction with SVR management, because (as previously mentioned) PVR as an isolated problem in a pre-operative ToF patient is rare due to protection of the pulmonary vasculature from high pulmonary blood flow by the RVOTO. However, marginal gains during significant spells can make a difference to the patient's oxygen saturation.•2) ;Administration of a high fraction of inspired oxygen (FiO•2 to normocarbia (high CO2 is a pulmonary vasoconstrictor) and ventilation strategies to recruit to the patient's functional residual capacity (FRC) volume to minimise PVR;Intubation and ventilation to control PaCO•Administration of pulmonary vasodilators such as inhaled nitric oxide (iNO);•Sedation and muscle relaxation to reduce oxygen consumption , 13.PVR reduction can be achieved via:2.4.RV diastolic function is often impaired in ToF patients due to RVH causing poor lusitropy , leading to a reduction in baseline diastolic function .Children with ToF are dependent on an increased venous return due to the increased RV end-diastolic pressure resulting from RVH. The demand for adequate venous return exists prior to surgery and persists following repair for several days to weeks; however, this does also impact the pre-repair patient. Optimising pre-load by ensuring appropriate volume resuscitation is vital in assuring ventricular filling, pulmonary blood flow, and cardiac output.2.5.In ToF, the RVOTO is often anatomically fixed at the valve level, but it can be worsened by sub-pulmonary valve muscle bundles that have the potential to contract or spasm, which can cause worsening acute arterial desaturation . Hyper-cSympathetic stimulation is often the precipitating factor; however, other factors can trigger these episodes see . The assSpelling children will present cyanosed and tachycardic and with cerebral agitation. Reduction in consciousness level or seizures can occur in patients with severe spelling attacks . CerebraThe goals in managing severe acute hyper-cyanotic episodes are (1) supportive treatment for the patient’s airway, breathing, circulation, and disability (reducing agitation); and (2) reduction of right-to-left shunt by breaking the spelling cycle by reducing dynamic RVOTO, decreasing PVR, and increasing SVR to raise LVEDP .•Administration of high-flow oxygen (needed to reduce the severity of the hypoxia);•Ensuring adequate analgesia ;•Bringing the knees to the chest (aiming to improve venous return);•Fluid bolus (improving venous return);•Increasing SVR ;•○Caution is needed, as induction of anesthesia can lower SVR, which may worsen cyanosisIntubation & ventilation •Use of β-blockers to reduce RVOT muscle bundle spasm;•○Extracorporeal life support (ECLS)○Surgical intervention .In cases of refractory hypoxia despite the above management, it is necessary to consider:The management of a spell includes:3.The aim for ToF patients is full surgical correction with VSD closure and relief of RVOTO, leaving an anatomically normalized heart. The age of repair varies, ranging from primary neonatal repair to young infants. There is debate regarding the most appropriate surgical management; however, there are some general concepts that are relevant to the paediatric intensivist .ToF repair requires cardiopulmonary bypass (CPB), and the general effects of CPB, cross-clamp time, bleeding, low cardiac output syndrome, and systemic inflammatory response should be managed following return to the PICU. Whilst rare in a ToF repair, significant low cardiac output (due to any cause) may require extracorporeal life support (ECLS) to support oxygen delivery. In these cases, early consideration should be given to cardiac catheterization or cardiac CT.in situ for an additional 24–48 h post-operatively due to the risk of pleural effusions. If complications occur, then the post-operative clinical course and PICU stay is prolonged.A typical fully corrected ToF repair patient usually experiences non-complex post-operative recovery and is often extubated early within 12–24 h, often requiring a minimal amount of intervention in the form of some volume requirement  and the use of cardiovascular support, as discussed below. Pleural drains are often left -Restrictive RV physiology;-Arrhythmias;-Residual lesions.There are some specific complications to ToF repair that can occur; these include:3.1.Restrictive RV physiology is defined as antegrade end-diastolic forward flow into the pulmonary artery . This anThe management of restrictive RV physiology post-ToF repair on the PICU is a common and important issue, as those with this physiology can have a low cardiac output and experience prolonged PICU admissions.•Low cardiac output state;•RV dysfunction (both systolic and diastolic);•High central venous pressures;•Pleural effusions ;•Ascites;•Liver and renal impairment.The management of this specific physiological state involves maintaining adequate RV pre-load and promoting diastolic filling in the RV , such as peritoneal dialysis .The theory of cardiopulmonary interactions would suggest that early extubation is beneficial for RV function, and this physiological theory would fit with a restrictive RV. However, the benefits of positive pressure ventilation (PPV) should be considered within the full clinical picture, and often a very sick child post-ToF repair benefits from PPV in terms of reduced oxygen consumption, allowing cooling, RRT administration, and improvement of oxygen delivery. Finding the balance can be difficult; however, multi-professional discussion with cardiology and cardiac surgical colleagues can support the decision-making process.3.2.Arrhythmias are common following ToF repair, with junctional ectopic tachycardia (JET) being the most common post-ToF repair. Sinus rhythm with atrio-ventricular synchrony should be maintained to provide adequate cardiac output.JET can be recognized by atrial and ventricular (AV) dissociation with an acceleration in ventricular rate, hemodynamic compromise, signs of low cardiac output, and development of cannon waves on the central venous pressure waveform. A 12-lead ECG  will confirm the diagnosis by showing a narrow complex tachycardia with AV dissociation and a faster ventricular rate . The ratThe management of JET, and many other tachyarrythmias, involves reducing sympathetic drive by ensuring adequate sedation, reducing inotrope/chronotrope use, and ensuring electrolytes  are maintained within normal limits. Cooling to normothermia can be helpful. Obtaining rate control of the JET using clonidine or dexmetatomadine and/or amiodarone may subsequently allow overdrive atrial pacing to allow AV synchrony to be achieved, if epicardial pacing wires have been inserted in theater. The amount of intervention required depends on the clinical impact on the patient's oxygen delivery and cardiac output. Some children can tolerate JET at a lower rate and others may need ECLS. This decision is made on a case-by-case basis using parameters such as blood pressure, lactate, urine output, and central venous oxygen saturations. The natural longevity of JET is that it will resolve in 10–14 days. It is important to note that JET cannot be cardioverted.Complete heart block can also occur in 3%–5% of patients, requiring dual-chamber epicardial pacing with recovery expected within 10 days. If this is not the case, permanent pacemaker insertion should be considered. It is important for the intensive care team to monitor pacing thresholds in these children, as rising thresholds may mandate earlier insertion of PPM or replacement of epicardial wires.3.3.•Residual VSD ;•Residual RVOTO;•Pulmonary valve regurgitation (expected after a transanular patch repair).Residual RVOT stenosis will limit pulmonary blood flow. In a case of repaired ToF in which the patient now has a closed VSD, there is no ability for right-to-left shunting. If residual RVOTO is demonstrated, an early discussion with cardiology and the cardiac surgical team is required to determine the best treatment strategy moving forward.In all congenital cardiac surgery, some residual lesions can occur, and in ToF this can include:In some ToF patients, when the pulmonary valve is incompetent or the RVOTO has been resected and repaired using a transannular patch, leaving a residual or absent pulmonary valve, blood flow during diastole can regurgitate back into the RV . This frEarly consideration should be given to cardiac catheterization or cardiac CT to look for residual lesions if the clinical course is not progressing as expected.4.It is uncommon for pediatric intensivists to be involved with corrected ToF patients following discharge from the PICU or hospital. Nevertheless, due to ongoing complications, they may be involved in the acute management of children presenting to the ED or pediatric cardiology wards. These complications can include requirement for pulmonary valve replacement to reduce pulmonary regurgitation, pleural effusions, heart failure, arrhythmias, and cardiac arrest .Corrected ToF patients are at high risk of ventricular arrhythmias, including VT and supraventricular tachycardia (SVT). Due to this risk, they may present to EDs in cardiac arrest with a VT etiology; management should involve ensuring that Resuscitation Council guidelines have been followed and that electrolyte imbalances have been corrected.5.ToF is one of the most common forms of congenital cardiac cyanotic lesion, and patients with this condition are admitted to PICUs following post-operative repair; however, those in extremis may present pre-operatively. It is vital for all pediatric critical care clinicians to understand the anatomical and physiological differences in ToF to enable them to apply appropriate interventions and to offer support to the referring hospitals when providing remote advice prior to retrieval.Post-operatively, there are several complications that are common across all cardiac patients who have received surgical intervention. Furthermore, there are specific complications relevant to ToF patients that should be considered when managing immediate and ongoing post-operative care within the PICU. It is also important to note that corrected ToF patients may present acutely to hospital as children and young adults, and PICU clinicians may be required to support the care delivered to these patients.


Walking is an important factor in daily life. Among older adults, gait function declines with age. In contrast to the many studies revealing gait differences between young adults and older adults, few studies have further divided older adults into groups. The purpose of this study was to subdivide an older adult population by age to identify age-related differences in functional evaluation, gait characteristics and cardiopulmonary metabolic energy consumption while walking.This was a cross-sectional study of 62 old adult participants who were classified into two age groups of 31 participants each as follows: young-old (65–74 years) and old-old (75–84 years) group. Physical functions, activities of daily living, mood state, cognitive function, quality of life, and fall efficacy were evaluated using the Short Physical Performance Battery (SPPB), Four-square Step Test (FSST), Timed Up and Go Test (TUG), Korean Version of the Modified Barthel Index, Geriatric Depression Scale (GDS), Korean Mini-mental State Examination, EuroQol-5 Dimensions (EQ-5D) questionnaire, and the Korean version of the Fall Efficacy Scale. A three-dimensional motion capture system  and two force plates  were used to investigate spatiotemporal gait parameters , kinematic variables , and kinetic variables  of gait. A portable cardiopulmonary metabolic system  was used to measure cardiopulmonary energy consumption.p < 0.05). Among spatiotemporal gait parameters, velocity, stride length, and step length were significantly lower in the old-old group than in the young-old group (p < 0.05). Among the kinematic variables, the knee joint flexion angles during initial contact and terminal swing phase were significantly higher in the old-old than the young-old group (P < 0.05). The old-old group also showed a significantly lower ankle joint plantarflexion angle during the pre- and initial swing phases (P < 0.05). Among the kinetic variables, the hip joint flexion moment and knee joint absorption power in the pre-swing phase were significantly lower in the old-old than the young-old group (P < 0.05).The old-old group showed significantly lower SPPB, FSST, TUG, GDS-SF, and EQ-5D scores . As the walking pace of old-old people diminishes, driving strength to move ahead and pressure on the knee joint also tend to decrease together with stride length. These differences in gait characteristics according to age among older adults could improve our understanding of how aging causes variations in gait that increase the risk of falls. Older adults of different ages may require customized intervention plans, such as gait training methods, to prevent age-related falls.Clinical trials registration information: ClinicalTrials.gov Identifier: NCT04723927 (26/01/2021).The online version contains supplementary material available at 10.1186/s12877-023-04088-6. The size of the global older adult population is rapidly increasing . The curAmong studies dealing with changes in older adults due to aging, gait studies are important because they can identify or predict clinical abnormalities related to aging . In gaitThe purpose of this study was to investigate differences in gait measures among participants divided into young-old (65–74 years) and old-old groups (75–84 years) within a single laboratory environment. Results are intended to be used as strategic data for creating elderly-specific interventions to prevent the risks associated with aging, such as falls. Three main hypotheses of this study are: 1) physical performance assessments and participant-reported outcomes differ between the young-old and old-old groups; 2) spatiotemporal gait parameters, kinematics, and kinetics differ between the young-old and old-old groups; 3) cardiopulmonary metabolic energy efficiency differ between the young-old and old-old groups.n = 31; 12 males) and old-old . Participants were excluded if they (1) experienced difficulty walking on their own due to issues such as visual field loss, (2) had severe dizziness that might cause a fall, or (3) demonstrated severe cognitive decline with a score of <  = 10 points on the Korean Mini-mental State Exam (K-MMSE) [This cross-sectional study included 62 older adult people without a history of neurological or psychiatric complaints ranging in age from 65–84 years . They were split into two groups based on their ages, as follows: young-old  . SamsungAll study participants who consented to participate provided their sociodemographic information , height, weight, body mass index, and medical history Table . FunctioThe physical performance assessments were as follows. The Short Physical Performance Battery (SPPB)  evaluate2, L/min) and carbon dioxide production  and thereby evaluates physical performance to support clinical diagnoses. Specifically, it measures the flow, quantity, and volume of oxygen and carbon dioxide in exhaled breath. Broadly, the equipment senses the amount of respiration sent to it by a sample line attached to a turbine when the exhaled gas is discharged through the turbine. Sensors within the device analyze the data. Prior to each experiment, the flow turbine and gas analyzer of the Cosmed K5 analyzer unit were calibrated using a 3-L calibration syringe, gas, and regulator.Scale Short Form (GDS-SF)  is an efandmarks . The motmentclass2pt{minimandmarks . The CosData were automatically converted to 3D coordinates using CORTEX motion capture software version 5.5.0 , which has a sampling rate of up to 2000 Hz for cameras and up to 5000 Hz for force plates. A low-band pass filter was used to remove unnecessary noise and better observe the changes according to gait cycle. All data were calculated for each gait cycle using Ortho Track 6.6.4 software . The net cardiopulmonary metabolic energy costs during standing and walking were calculated using the Brockway equation as follows: O2-5.90N , which sO2-5.90N . EEm andAll statistical analyses were performed using SPSS version 22.0 , and the significance level was set at 0.05. Results were calculated as the mean value with standard deviation. To determine the appropriate statistical tests to apply, we checked the distribution of the data for normality. Differences in demographic characteristics between the young-old and old-old were investigated using independent t-tests and chi-square tests. Significant variations in functional assessments, spatiotemporal gait parameters, kinematics and kinetics of gait, and cardiopulmonary metabolic energy efficiency were compared using paired t tests or the Mann–Whitney U test to determine statistically significant differences among groups.P < 0.01). Moreover, the quality of life (EQ-5D) and mood state (GDS) of the old-old group were significantly lower than those of the young-old group (P < 0.05). However, there were no significant differences between the two groups in K-MMSE, K-MBI, and FES-K scores.Table P < 0.05) . The ankle joint angle was less plantarflexed during the pre- and initial-swing phases of the gait cycle in the old-old group than in the young-old group (P < 0.01). The results of comparative analysis of kinetic moment and power gait characteristics of the two groups can be seen in Fig. P < 0.05). Knee and ankle moments did not differ significantly between groups. There was a difference between the young-old and old-old groups in peak knee joint power in the pre-swing phase; the old-old group used significantly less absorption power than the young-old group (P < 0.05). Hip and ankle power did not exhibit any substantial differences between groups. The peak ground reaction force during the gait cycle did not differ significantly between groups  Fig. . The gro05) Fig. . The kneTable In this study, we investigated differences in gait characteristics and cardiopulmonary metabolic energy consumption during walking between young-old (65–74 years) and old-old (75–84 years) participants using a 3D motion capture system and a wearable cardiopulmonary energy measurement system.Physical performance according to SPPB score was lower in the old-old group than the young-old group, and the FSST and TUG results were slower in the old-old group than the young-old group. In the mood state and quality of life assessments, the GDS-SF score of the old-old group was higher and the EQ-5D score significantly lower than those in the young-old group. Older people with a slower gait speed move at a slow pace when performing daily tasks such as moving from sitting in a chair to standing and walking. Those changes are caused by a decline in muscle strength, reduced physical exercise, joint pain, and fear of falling –48. PrevAnalysis of spatiotemporal gait parameters showed that the old-old group tended to walk at a slower speed and use shorter step length and stride length than the young-old group. Research suggests that walking speed has a positive correlation with step length and stride length in older adults . Older aThe study's kinematic findings indicated that the old-old group tended to have greater knee flexion upon heel contact than the young-old group. A prior study suggested that a reduced extension angle of the knee joint during initial contact in older adults is linked to weaker quadriceps muscles, knee pain, and slower walking speed , 54. NotAging reduces the hip extension moment during the loading response phase . In thisIn cardiopulmonary metabolic energy consumption, despite walking slower than the young-old group, the old-old group used a similar amount of energy in terms of net VO2, EEm, and MET during preferred walking speeds on the treadmill. One possible explanation for the lack of statistically significant difference between the groups is that the average age of the old-old group was 77.74 years, which isn’t much older than 75; another possible reason is that this study recruited very healthy old-old participants.This study has some limitations. First, although aging affects both gait pattern and muscle activity, this study did not measure muscle activity. In a future study, muscle activation of the lower limbs should be measured alongside kinematic and kinetic data. Second, this study did not calculate rigid body model and COM variables. Therefore, future studies should consider specific variables that describe the essential characteristics of movement. In addition, data should be collected for young adults and the oldest-old population (85 +) to compare age-related gait changes more comprehensively.In this study, the old-old group had lower functional assessment scores, increased knee flexion angle, impaired ankle joint motion, and insufficient hip and knee joint kinetic values while walking compared to the young-old group. These results will contribute to the development of personalized intervention plans for older adult individuals of varying age to prevent age-related gait issues like falls.Additional file 1: Supplementary Table S1. Kinematic joint angle differences between the young-old and old-old groups. Supplementary Table S2. Kinetic peak joint moment differences between the young-old and old-old groups. Supplementary Table S3. Kinetic peak joint power differences between the young-old and old-old groups. Supplementary Table S4. Self-selected treadmill walking speed and distance in the young-old and old-old groups. Supplementally Figure S1. Peak ground reaction force over a gait cycle did not differ significantly between the young-old and old-old groups. IC: Initial contact (0–2%), LR: Loading response (2–12%), MS: Mid-stance (12–31%), TS: Terminal stance (31–50%), PSw: Pre-swing (50–62%), ISw: Initial swing (62–73%), MSw: Mid-swing (73–87%), TSw: Terminal swing (87–100%).