In clinical practice, we encounter ischemic cardiomyopathy (ICM) with underlying viable, dysfunctional myocardium on a regular basis. Evidence from the Surgical Treatment for Ischemic Heart failure (STICH) and its Extension Study is supportive of improved outcomes with coronary revascularization, irrespective of myocardial viable status. However, Dobutamine stress echocardiography (DSE) and single‐photon emission computed tomography (SPECT), used in STICH to assess myocardial viability may fail to distinguish hibernating myocardium from scar due to suboptimal image resolution and poor tissue characterization.Cardiac magnetic resonance (CMR) and positron emission tomography (PET) can precisely quantify myocardial scar and identify metabolically active, viable myocardium respectively. Unlike DSE and SPECT, CMR and PET allow examining myocardial status as a contiguous spectrum from viable to partially viable myocardium with varying degrees of subendocardial scar and nonviable myocardium with predominantly transmural scar, the therapeutic and prognostic determinants of ICM.Under the guidance of CMR and PET imaging, myocardium can be distinguished viable from partially viable with subendocardial scar and predominantly transmural scar. In ICM, optimal medical therapy and coronary revascularization of viable/partially viable myocardium but not transmural scar may improve outcomes in patients with acceptable procedural risk.Coronary revascularization of partially viable and viable myocardial territory may improve clinical outcomes by preventing future ischemic, infarct events and further worsening of left ventricular remodeling and function.When deciding if coronary revascularization is appropriate in a patient with ICM, it is essential to take a patient‐tailored, comprehensive approach incorporating myocardial viability, ischemia, and scar data with others such as procedural risk, and patient's comorbidities. 1.Viability of myocardium is assessed by different imaging modalities, probing different characteristics of the living myocyte – uptake of radioactive isotope, TC‐99m or Tl‐201 (SPECT MPI), contractile reserve , metabolic properties (FDG uptake on PET), absence of scar (CMR).2.Dysfunctional, viable myocardium as compared to nonviable myocardium carries a better prognosis with appropriate therapy.3.Dysfunctional myocardium may not be simplified into a binary state of viable or not. It can be a continuum process, with a myocardial segment in a hybrid state with an intermix of viable myocytes in early to late phases of hibernation and fibrosis.4.Nonviable myocardium on Dobutamine Stress Echocardiography or SPECT Nuclear imaging may be partially viable (with varying degrees of fibrosis) or viable with no scar, on CMR.5.Coronary revascularization of partially viable or viable myocardium should be considered if the procedural risk is acceptable, as it improves long‐term outcomes by preventing further myocardial ischemia/infarction and possibly improving left ventricular function and remodeling. Ischemic ventricular dysfunction and remodeling with viable myocardium (VM) or partially viable myocardium (PVM) may have better outcomes when they receive appropriate therapy including coronary revascularization compared to those with predominantly fibrotic, nonviable myocardium (NVM).Myocardial ischemia leads to stunning, myocyte apoptosis, necrosis, inflammation, and fibrosis Figure . Two typThe following sections of the paper discuss ‐ evaluation of myocardial viability by multimodality imaging, prognostic implications of VM, PVM, NVM; therapeutic decision making in ICM based on viability, left ventricular function, and remodeling.2In conventional clinical practice ‐ myocardium with contractile dysfunction is termed “VM” if it is predicted to recover contractility with medical therapy and coronary revascularization (CorR). However, with appropriate medical therapy and CoR, improved clinical outcomes may be noted despite the lack of a significant improvement in LV function.Current myocardial viability imaging techniques interrogate structural and functional integrity of the cardiac myocyte and its intracellular processes; end‐diastolic wall thickness on echocardiography (Echo) or cardiac magnetic resonance (CMR), contractile reserve assessment with low dose dobutamine by Echo or CMR, cell membrane integrity based on radioactive tracer uptake on single‐photon emission computed tomography (SPECT), ischemic myocardial metabolic properties (cellular glucose uptake) by positron emission tomography (PET), and late gadolinium hyper‐enhancement and T1 mapping  by CMR. When VM is defined in a traditional way as the myocardium with improved functional recovery post revascularization, tests (dobutamine Echo and CMR) that evaluate contractile reserve possess higher positive predictive value and specificity but lower sensitivity in comparison to those that estimate cell membrane integrity (SPECT) and metabolic (PET) properties, which are known to have higher negative predictive value and sensitivity but lower specificity.Useful modalities in viability assessment in the clinical practice are discussed below Table .3The ECG is an initial tool in the evaluation of viability. While the absence of pathologic Q‐waves may be suggestive of viable myocardium4Normal segmental thickness (>6 mm) hints of VM and severely thinned (4 mm or less) segments may be suggestive of NVM or PVM. Normal end‐diastolic wall thickness was shown to have a high sensitivity (>90%) and low specificity (<50%) in a meta‐analysis in predicting LV contractile recovery.5Stress echocardiography using low dose Dobutamine to elicit contractile response in viable segments with systolic dysfunction, is a low risk, quick, noninvasive test with no radiation risk. VM with a contractile reserve in a minimum of >5 segments, increases the success rate of functional recovery following coronary revascularization.5.1Typically, to induce a contractile response in baseline dysfunctional segments, Dobutamine is started at low doses (2.5–5 μg/kg/min) and gradually increased to intermediate doses (up to 20 μg/kg/min). Subsequently, to assess ischemic response, infusion is incrementally increased to stress doses (up to 40 μg/kg/min), with the addition of IV Atropine as needed (up to 2 mg in divided doses), to achieve a target heart rate (85% (220‐age). Under close hemodynamic and EKG monitoring, Dobutamine is infused for 3 min at each stage but infusion time can be variable based on patient's hemodynamics and contractile response.Four distinct responses to dobutamine stress have been described. A biphasic response, in which contractility improves with low dose dobutamine and worsens at higher doses due to ischemia has been shown to be 60% sensitive and 88% specific in predicting contractile recovery 6 weeks after coronary revascularization.DSE is widely available, accessible and inexpensive with no radiation risk. If the positive contractile reserve is demonstrated on DSE, it is a specific sign of VM. However, the absence of contractile reserve on DSE may not preclude viability in advanced stages of thinned, hibernating myocardium. Limitations of DSE include poor acoustic windows and other technical difficulties in image acquisition that may result in images of suboptimal, non‐diagnostic quality.6In SPECT imaging, VM is illustrated from detecting the positive uptake of the radionuclide‐labeled tracer by a myocyte with an intact cell membrane. An arbitrary cutoff > 50% tracer activity  of the maximum uptake of a normal segment, has been used to identify VM, 30%–50% suggests PVM (moderately reduced counts) and < 30% indicative of NVM (severely reduced to absent counts). When rest perfusion defect is suggestive of equivocal viability, stress perfusion imaging may be helpful, as a worsening defect on stress (ischemic response) would be indicative of PVM/VM. In addition, relatively intact wall motion and thickening at rest or improved segmental function on poststress gated imaging would be a strong marker of the absence of transmural myocardial scar.201Tl  and 99mTc. ASNC 2018 SPECT imaging guidelines provide a detailed description of rest/stress perfusion imaging of 99mTc and stress/rest, 4/24 h delayed redistribution imaging of 201 Tl with or without reinjection.The most common tracers used in SPECT myocardial perfusion imaging are 6.1201 Tl is driven by blood flow state at rest whereas the subsequent uptake over next 4–24 h is determined by “refill and redistribution” of the isotope, determined by cellular membrane integrity.201Tl) from redistribution of the 201Tl. Sensitivity of viability detection on 201Tl imaging may increase in late (24 h) reinjection/redistribution protocol compared to 4 h early redistribution protocol. Radiopharmaceutical activity of 201T (t ½ 73 h) in rest/redistribution imaging is approximately 3mCI with a corresponding radiation effective dose of 10–15 mSV.The initial myocardial uptake of 6.299m myocardial uptake is dependent on a passive cell membrane diffusion and mitochondrial retention with no redistribution property. Rest and stress perfusion imaging are typically performed the same day, however, a 2‐day protocol may be used when higher tracer doses are required for both rest and stress, to overcome a suboptimal image quality from soft tissue attenuation (from a large body habitus). Radiopharmaceutical activity of Tc99m (t ½ 6 h) for rest imaging is approximately 10 mCI (2–3 mSv), typically a 1/3 of stress imaging, in same day rest/stress protocol. After injecting Tc99m, approximately 30–60 min wait time is allowed before imaging the heart, to increase the clearance of subdiaphragmatic tracer activity and reduce the incidence of artifacts as a result of. Soft tissue attenuation and motion artifacts may appear as perfusion defects that can be overcome by using attenuation and motion correction software. Imaging in prone positioning may help in eliminating a diaphragmatic attenuation artifact.Tc99mTc‐sestamibi is its much shorter protocol. Even though Tl is considered superior to Tc imaging due to its redistribution feature, studies have shown that both are comparable in diagnostic accuracy in detecting VM.201Tl were demonstrated to be 86% and 59%, respectively, for predicting functional recovery after revascularization and 81% and 66% for Tc99m, respectively.When an artifact is ruled out, a perfusion defect at rest on Tc imaging is either an infarct  or hibernating myocardium Figure . A furthSPECT imaging is easily available and lower cost as compared to PET imaging. While normal uptake of radioactive tracer confirms the viability of myocardium, absence of tracer uptake does not confirm nonviable, transmural myocardial scar, as discussed below.7NVM by SPECT and Echo imaging techniques has been conventionally assumed as myocardial scar in totality. Lack of superior resolution to detect radioactive isotope uptake by thinned viable myocardium on SPECT and absence of contractile reserve in thinned non‐fibrotic myocardial segments on Echo may result in labeling of VM or PVM as NVM. Myocytes of the early hibernating phase coexisting with those in late stages may appear as a perfusion defect with <50% radioactive isotope activity of a normal segment. Differential characterization of NVM on SPECT and Echo would be (1) thinned, advanced stages of hibernating myocardium Figure , (2) a m8PET imaging uses the preserved metabolic property of viable myocardium as opposed to the absence of metabolic activity in the scar. Superior resolution, quick imaging, absolute quantification of myocardial perfusion, and less radiation exposure are a few advantages of PET over the SPECT.82Rb) to assess perfusion and F18‐Fludeoxyglucose (18F‐FDG) to evaluate myocardial glucose metabolism.Cardiac PET uses N‐13 ammonia or Rubidium‐82  levels before injecting 18F‐FDG. Suboptimal patient preparation may yield poor, non‐diagnostic images. Preparation of diabetic patients can be particularly challenging, requiring insulin injection to overcome myocardial insulin resistance and may take longer wait times from injecting 18F‐FDG to image acquisition. PET imaging is performed about 45–90 min (up to 3 h in diabetics) after injecting approximately 10 mCi (7 mSv) of 18F‐FDG (t ½ 110 min). For the purpose of attenuation correction, low resolution, nongated CT transmission scanning is performed afterwards. ASNC 2016 guidelines provide a detailed description of the patient preparation and PET imaging protocols.For optimal 18F‐FDG. Normal rest perfusion imaging confirms viability by demonstrating intact myocyte cell membrane, eliminating the need for metabolic imaging. VM is characterized by reduced resting perfusion and preserved 18F‐FDG uptake.Viability testing by PET consists of rest imaging with perfusion tracer and metabolic imaging with 9Ability to directly image and estimate the scar burden, myocardial perfusion, segmental wall motion, thickness, and contractile reserve with dobutamine infusion, left ventricular ejection fraction, and ventricular volumes,9.19.1.1Gadolinium contrast is rapidly cleared from normal myocardium within 10 min of injection. However, in case of myocardial scar, the contrast is trapped with a delayed clearance from the increased interstitial space. In LGE CMR sequence, while the normal myocardium with no contrast retention is nulled (dark appearance), myocardial scar appears bright from retained contrast.9.1.2If LGE is <50% of segmental thickness or if myocardium is severely thinned and akinetic, the predictive accuracy of functional recovery with therapy can be further enhanced by demonstrating contractile reserve with low dose dobutamine.2, gadolinium‐based contrast media (GBCM) may be relatively contraindicated due to the risk of nephrogenic fibrosing sclerosis (NFS). However, a joint consensus statement from the American college of Radiology and the National kidney foundation advocates a more liberal use of Group II and Group III GBCM, by weighing potential benefits of GBCM based MRI study versus extremely low risk of NSF.Updated version of CMR standardized protocols from 2020 provide, further details of LGE imaging.In the STICHES trial (7), no significant contractile recovery of dysfunctional myocardium was demonstrated in the group  despite improved outcomes – a finding that suggests any residual myocardium in the absence of transmural scar may benefit from CorR.9.2Other imaging techniques and markers ‐ Myocardial contrast echocardiography (microvascular integrity assessment), speckle echocardiography , and Cardiac CT , have been studied to assess myocardial viability.10Viability testing appears to be most helpful when it is uncertain that the myocardial segment (s) in question is predominantly transmural scar or otherwise, due to the clinical implications of better prognosis of dysfunctional PVM and VM by medical therapy and CorR.If the dysfunctional myocardial segment possesses relatively preserved thickness with wall motion no worse than hypokinesis and absence of Q waves on EKG, it is unlikely that segment is NVM (scar), precluding need for any further testing to assess viability.Viability testing should be tailored to the individual patient based on several factors including limitations or contraindications of a particular study in each patient, local expertise, and availability.The degree of LV remodeling and dysfunction may play a role in deciding which test to perform. Patients with extreme degrees of LV dilatation and segmental wall thinning may need an advanced imaging modality  that could distinguish PVM from NVM (scar). In patients with mild to moderate degree of LV dysfunction and remodeling, dobutamine stress Echo and SPECT imaging may suffice.11Ischemic cardiomyopathy subjects with VM appear to have a better prognosis with medical therapy and CorR compared with those with large amounts of scar burden who are at higher risk for heart failure and ventricular arrhythmias.The Surgical Treatment for Ischemic Heart Failure (STICH), a prospective, randomized study examined 5‐year mortality outcomes in severe, ischemic LV dysfunction (EF < 35%) in the surgical revascularization and medical therapy arm as compared with medical therapy alone group and found no difference. A viability sub‐study found no interaction between the viability status of myocardium and the clinical outcomes. Subsequently, the STICH Extension Study (STICHES), a 10‐year long‐term follow‐up study found improved mortality outcomes in surgical revascularization group; however, yet again the viability sub‐study of STICHES showed no association of myocardial viability status with the outcomes. In addition, improved outcomes were noted to be independent of improvement in LV systolic function.How to reconcile the above findings has been an intense debate as it goes against the logic that dysfunctional myocardium with diminished perfusion when rescued with CoR, should translate into improved outcomes ‐ an established notion supported by wealth of prior observational data. A close examination of STICH study patient population, limitations of methods and imaging techniques used for viability, and further follow‐up LVEF assessment may provide a few clues.To begin with, the findings may not be reproducible with generalized applicability as the viability sub‐study of STICH was a non‐randomized, non‐blinded, underpowered study with a small number of subjects with NVM. In this patient population with a severely dilated and dysfunctional LV with thinned and severely hypokinetic to akinetic segments, simply classifying myocardium as viable or nonviable in a binary fashion with no appreciation of varying degrees of PVM that may influence the outcomes of therapy might have led to these findings that can't be explained in a clinically intuitive sense. Moreover, SPECT or dobutamine echocardiography imaging techniques used in STICH study lack the ability to directly image myocardial scar and characterize and distinguish the thinned myocardium as hibernating versus subendocardial or transmural scar, as each portends a different prognostic significance.The LVEF improvement with therapy that was claimed to be not associated with improved outcomes in STICHES trial was minimal (2%), that may be statistically but not clinically significant. In addition, a single follow‐up LVEF measurement was performed a bit prematurely at 3 months, as therapy may take a considerably longer time (>3–6 months) to result in a meaningful improvement in EF (>5%) in a severely dilated, dysfunctional LV.Plausible underlying mechanisms for the improved outcomes noted in surgical revascularization group in STICHES are: 1. CoR may prevent acute MI and complications, salvaging any further damage of VM and PVM (31). Trials comparing CABG versus PCI and the ISCHEMIA trial support the fact that CorR reduces future spontaneous myocardial infarction (MI) (32–34). 2. Improvement in LV systolic function (EF) from CoR over the long‐term (35). 3. Revascularization may not improve resting LVEF when baseline LV remodeling and systolic function is severely reduced, however, CoR may aid in preserving myocardial contractile reserve with stress/exercise. 4. CoR may reduce the excitability of arrhythmogenic foci and incidence of ventricular arrhythmias.The deterministic nature of the myocardial viability status on clinical outcomes of revascularization in ischemic cardiomyopathy has been observed in a few prospective studies.12Due to the conflicting and controversial data as noted above, there has been an ongoing debate regarding viability testing and CorR in patients with ischemic left ventricular dysfunction Figure .We must keep in mind that many other factors such as clinical symptomatology, procedural risk, anatomical extent and complexity of CAD, degree of LV remodeling – should be considered besides myocardial viability and left ventricular scar burden information in making the CorR decision.12.1When dysfunctional myocardium is determined as viable by any testing modality, prognostic outcomes improve with CorR of anatomically corresponding coronary territory. This is applicable in both mild to moderate (EF > 35%) and severe (EF < 35%) LV dysfunction and remodeling.In ischemic cardiomyopathy with advanced LV systolic dysfunction, it is essential to optimize medical therapy and take a multitude of factors; presence or absence of angina, degree of myocardial ischemia, the extent of scar burden in the territory of anatomical CAD, LV adverse remodeling, LVEF, patient's comorbidities, and procedural risk into consideration before coronary revascularization.In general, left ventricular hibernating myocardium of approximately 20% of LV mass may be needed to make a meaningful impact in LV function improvement (at least >5% LVEF) after CorR.12.2When myocardium is noted as NVM on SPECT nuclear or echocardiography but there is a suspicion of PVM based on clinical, EKG and other imaging parameters, it would be reasonable to use CMR to confirm if the NVM is predominantly scar versus PVM. After optimizing medical therapy, If the patient's surgical risk is acceptable, CorR of the myocardial segments with PVM with no transmural scar should be considered.12.2.1Myocardium may be noted as NVM on SPECT or Echo, however, at times, no advanced imaging  is feasible due to either contraindication, lack of availability, or affordability. As discussed earlier, the possibility of labeling VM or PVM as NVM on Echo and SPECT is not uncommon. In addition, as mentioned above, ICM patients from STICHES study who underwent surgical CorR benefited regardless of viability status on SPECT or Echo. In these circumstances, it would be prudent to make the decision by a multidisciplinary team of a general cardiologist, an interventional cardiologist, a cardiac surgeon, an advanced cardiac imager, and a heart failure expert to discuss each patient on a case‐to‐case basis. In addition to myocardial viability status, patients should be evaluated for the degree of myocardial ischemia, LV adverse remodeling, LV dyssynchrony, and associated functional mitral and tricuspid insufficiency. In severe LV dysfunction (EF < 35%), patients should also be assessed for the feasibility and eligibility for other advanced therapeutic options such as cardiac resynchronization therapy, Mitral/Tricuspid valve intervention for functional insufficiency, LV assist device where appropriate, with or without CorR. When considering for CorR, it is most important to take the patient's functional status, symptomatology, and comorbidities into account and assess the overall procedural risks versus benefits of CorR. For instance, CorR may be appropriate in a patient with chest pain symptoms, evidence of myocardial ischemia, PVM/VM on SPECT/Echo with low to intermediate procedural risk; however, the risk of CoR may counterbalance or even outweigh the benefits, in a patient with no ischemic symptoms, advanced CHF with a severely remodeled LV and notable surrogate markers of myocardial scar such as akinetic, thinned myocardium on Echo, absent radioactive tracer uptake on SPECT and q waves on EKG.12.3Revascularization of predominantly scarred or metabolically inactive segments may not be warranted as it is not expected to improve the outcomes.13Dysfunctional myocardium should not be distinguished as a binary state, viable or nonviable as it is rather a continuum, ranging from early stages of hibernation with minimal LV remodeling and no fibrosis to an intermediate phase of thinned, partially viable, and partially fibrotic state and finally a terminal, primarily a fibrotic phase.Further research has been ongoing to understand and precisely characterize myocardial ischemia, fibrosis, and LV remodeling and their interaction with a variety of therapeutic strategies in predicting the outcomes. Novel treatment approaches such as stem cell therapies for ICM are under investigation.No financial or nonfinancial interests are directly or indirectly related to the work submitted for publication.Supplementary Table 1 Comparison of Imaging Techniques of Myocardial viability Testing.Click here for additional data file.


For valid accelerometer-assessed physical activity (PA) data, several methodological aspects should be considered. We aimed to 1) visualize the applicability of absolute accelerometer cut-offs to classify PA intensity, 2) verify recommendations to measure PA over 7 days by examining inter-day variability and reactivity, 3) examine seasonal differences in PA, and 4) recommend during which 10 h day period accelerometers should be worn to capture the most PA in patients with heart failure (HEART) and healthy individuals (HEALTH).Fifty-six HEART  and 299 HEALTH  of the COmPLETE study wore accelerometers for 14 days. Aim 1 was analyzed descriptively. Key analyses were performed using linear mixed models.The results yielded poor applicability of absolute cut-offs. The day of the week significantly affected PA in both groups. PA-reactivity was not present in either group. A seasonal influence on PA was only found in HEALTH. Large inter-individual variability in PA timing was present.Our data indicated that absolute cut-offs foster inaccuracies in both populations. In HEART, Sunday and four other days included in the analyses seem sufficient to estimate PA and the consideration of seasonal differences and reactivity seems not necessary. For healthy individuals, both weekend days plus four other days should be integrated into the analyses and seasonal differences should be considered. Due to substantial inter-individual variability in PA timing, accelerometers should be worn throughout waking time. These findings may improve future PA assessment.NCT03986892).The COmPLETE study was registered at clinicaltrials.gov (The online version contains supplementary material available at 10.1186/s12874-021-01350-6. Physical activity (PA) is of major importance for healthy aging , 2 as weWhen assessing PA, many methodological decisions need to be made regarding data processing as well as data collection. Such aspects include for example which cut-off values to use to determine different categories of PA intensities or for how many days subjects will be monitored. Bearing in mind that as little as 15 min of moderate PA per day reduce all-cause mortality and increase life expectancy , small iFirstly, cut-off values are used to enable the classification of performed activities into light, moderate, or vigorous intensity of PA  and are usually linked to more coherent units such as metabolic equivalents (METs) . Howeverentclass1pt{minima context . It dire context , 12.Secondly, to obtain a representative picture of real-life PA patterns, the most recent recommendation for healthy individuals suggests the inclusion of at least four weekdays and one weekend day . Hence, Thirdly, the season of the year  and the inherent weather conditions  have been shown to affect PA levels in a variety of age groups of the general population using numerous self-reported and objective tools , 19. AgaFourthly, when PA is measured in research, the term wear time compliance is used to describe how long the devices were worn by the subjects. Since it is difficult to achieve 100% wear time compliance, it was generally accepted over the last decade that a minimum wear time of 10 h per day provides a valid estimate of daily PA. Although the current consensus is that all data exceeding this threshold are included in the statistical analyses , 8, 20, Accordingly, the aims of this study were 1) to illustrate the PA classification accuracy of current absolute accelerometer cut-offs in relation to cardiorespiratory fitness 2) to assess differences between weekdays and weekend days as well as reactivity over a period of 14 days, 3) to examine the influence of the season of the year on PA patterns, and 4) to determine during which 10 h period during the day subjects are the most active.The COmPLETE study is a cross-sectional study conducted between January 2018 and December 2019 at the Department of Sport, Exercise and Health at the University of Basel, Switzerland and is registered at clinicaltrials.gov (NCT03986892). The study aimed to perform a comprehensive assessment of components of physical fitness and cardiovascular function in HEART and healthy individuals (HEALTH) as well as to identify the most important factors contributing to healthy aging . More den = 56) and HEALTH (n = 299). A full description of the recruitment procedures can be found elsewhere [.m−2, and aged between 20 to 100 years. Exclusion criteria were: manifested exercise limiting chronic disease , pregnancy or breastfeeding, drug or alcohol abuse, hypertonic blood pressure > 160/100 mmHg, compromising orthopedic problems, Alzheimer’s disease or any other form of dementia, and inability to follow the procedures of the study [This study includes both, HEART  (1) [PA was objectively assessed using the GENEActiv triaxial accelerometer  . The parg) (1) .1\documeFor a reliable assessment of LPA, MPA, and VPA, only subjects with wear time ≥ 10 h per day , 20 and 2-values at any point during the test (30 s mean).Cardiopulmonary exercise testing was performed on a magnetically braked bicycle ergometer  following one of five ramp protocols described in detail elsewhere . The appSD unless stated otherwise. Figures are shown as mean ± SE. For Fig. P = 0.05 for two-sided tests.All statistical analyses were performed in R. Figures were made with GraphPad Prism version 9.0.2. Data in text and tables are presented as mean ± The flowchart is visualized in Fig. For 5.1% of HEART, the cut-off for VPA (6 METs) was set too low, as this absolute intensity corresponded to MPA in relative terms. Yet, for 51.9%, the cut-off value was above their entclass1pt{minimaentclass1pt{minimaP < 0.001), but not VPA and sedentary time. Among HEALTH, all PA intensities including sedentary time were significantly affected by this factor . Estimates ± SE and 95% CI for all days and the respective PA intensities are available in Additional file P < 0.001; see Fig. P < 0.001) in HEART but not in HEALTH. There was little evidence supporting the presence of reactivity throughout the 13-day measurement period in none of the PA patterns in either group (P > 0.05).Detailed analyses of PA patterns of both HEART and HEALTH according to the day of the week are displayed in Fig. P < 0.001), MVPA (P = 0.011), MPA (P = 0.006), LPA (P < 0.001), and sedentary time (P = 0.012) but not for VPA  was apparent.The measurement period had no impact on wear time compliance in HEART. Yet, for HEALTH, a significant but non-relevant reduction in wear time compliance for each progressing measurement day  on this day compared to all other days, except Friday. Consequently, for patients with heart failure, the inclusion of Sunday but not Saturday may be necessary to obtain a reliable picture of the population’s PA. Combining the recommendations of Dillon et al.  for healThe discrepancies regarding PA behavior on Saturday between healthy individuals in this study and the data of Ricardo et al.  suggest Exploratively, we analyzed MVPA when only minutes accumulated in ≥ 10 min bouts were considered to see how structured activities/sports change. When comparing single minute counts with ≥ 10 min bouts see Fig.  no diffeFinally, there was little evidence for reactivity in any of the PA intensities or sedentary behavior neither for patients with heart failure nor for healthy individuals. For studies that aim to obtain a representative picture of the general population’s PA, it seems appropriate to use the first 7 days the device is worn. No adjustment for reactivity seems necessary in both populations.Seasonal differences in objectively measured PA are commonly described in healthy individuals with less activity in winter compared to summer . KlompstThis study provides little evidence that wear time compliance is affected to a relevant extend by the duration of the measurement period. Regarding the significant association of wear time with the measurement day, estimates were only minor and de facto not relevant.Finally, Fig. Limitations of this study were, firstly, that no accelerometer data were available during the cardiorespiratory exercise testing since it was performed on a bicycle ergometer, thus only allowing a theoretical calculation of classification accuracy of absolute cut-offs. Secondly, the strict criteria used to define a valid day may have led to the inclusion of particularly compliant participants. On the other hand, these criteria may have yielded accurate PA estimates for both weeks. Thirdly, the cross-sectional study design may have limited the validity of the analyses regarding seasonal differences. Fourthly, Fig. To conclude, absolute cut-offs constitute a source of error for PA classification and her days  should bher days . SeasonaAdditional file 1: Table 1. Linear mixed model results with estimates of daily physical activity (min) ± SE for patients with heart failure and healthy individuals. Table 2. Linear mixed model results with estimates of daily physical activity (min) ± SE for patients with heart failure and healthy individuals. Figure 1. Cardiorespiratory response in % of


Survival of pediatric patients with heart failure has improved due to medical and surgical advances over the past decades. The complexity of pediatric heart transplant patients has increased as medical and surgical management for patients with congenital heart disease continues to improve. Quality of life in patients with heart failure and transplant might be affected by the impact on functional status that heart failure, heart failure complications or treatment might have. Functional areas affected might be motor, exercise capacity, feeding, speech and/or cognition. The goal of rehabilitation is to enhance and restore functional ability and quality of life to those with physical impairments or disabilities. Some of these rehabilitation interventions such as exercise training have been extensively evaluated in adults with heart failure. Literature in the pediatric population is limited yet promising. The use of additional rehabilitation interventions geared toward specific complications experienced by patients with heart failure or heart transplant are potentially helpful. The use of individualized multidisciplinary rehabilitation program that includes medical management, rehabilitation equipment and the use of physical, occupational, speech and feeding therapies can help improve the quality of life of patients with heart failure and transplant. The development of advanced heart failure management strategies and associated need for heart transplantation in pediatric patients is increasing survival in pediatric patients with congenital heart disease. This increase in survival will often be accompanied by suboptimal quality of life and functional outcomes. Multidisciplinary rehabilitation programs will be critical to improve patient outcomes.Heart failure is a complex clinical syndrome of inappropriate oxygen delivery secondary to a number of physiologic derangements. These typically include congenital or acquired heart disease with volume or pressure overload, inappropriate systolic function, inappropriate diastolic function or inappropriate blood oxygen carrying capacity . AdvancePrecise documentation of the incidence and prevalence of heart failure in pediatric patients has been elusive, though significant demographic and geographic differences in epidemiology are evident. Incidence has been reported to range from 0.87/100,000 in the UK and Ireland while 7.4/100,000 in Taiwan . The undA recent query from our group of the Organ Procurement and Transplantation Network (OPTN), the American governmental entity overseeing transplantation, noted 1,789 pediatric heart transplant candidate (<18 years old) listings during a 33-month period between 2016 and 2019 , patients <1 year of age undergoing heart transplantation had congenital heart disease 72% of the time between 1988 and 2004, while only 57% did between 2010 and 2018 .It is notable that though the staged palliation of patients to Fontan circulation has resulted in improved survival for these patients  they conOnce listed for heart transplant patients must wait for a donor heart variable amounts of times depending on a number of important variables including listing status, size, sensitization and blood type, among others. The number of children listed for heart transplantation is higher than the number of available donor organs, resulting in increasing waitlist times, particularly for children between 10 and 25 kg in weight and those with O blood type . The adoVentricular assist devices have been increasingly used in children waiting for heart transplantation with resulting reductions in waitlist mortality . As techThe overall outcomes for pediatric heart transplant recipients are excellent, with 5-year and 10-year post-transplant survival approaching 80 and 65% respectively. It is notable that outcomes are also improving over time, with those in the most recent era (2010–2017) having 1-year post-transplant survival of ~90% compared to just below 70% for those in the earliest era (1982–1991), owing primarily to improvements in the operative, perioperative and early post-transplant management including improvement in immune suppression . One appA number of other important factors affect median survival including age, rejection, presence of CHD and pre-transplant need for mechanical support, among others. Patients <1 year of age at transplantation have the highest perioperative mortality risk, however they also enjoy the lowest rate of graft loss over time, leading to the longest median survival, currently over 20 years . PatientIn addition to the evolving improvements in outcomes across the board for pediatric heart transplant patients, >80% of post-transplant patients have minor to no activity restrictions, based on Lansky scores when evaluated at 1, 2, and 3-years post-transplant . While tGenerally, when rehabilitation is discussed in patients with heart failure or heart transplant, the focus has mainly been around exercise capacity and exercise training. However, there are other areas of function that might be impacted due to their cardiac function, comorbidities/complications related to heart failure and treatment for heart failure. As mentioned previously the complexity of cases of CHD that get a heart transplant has increased.Parents of children with CHD commonly report these children experience difficulty with learning, communication, self-care, fine and gross motor skills. Additionally, these children miss more days of school and participate in less extracurricular activities than children with special healthcare needs without heart disease . ChildreThere are four main areas of function: gross motor related to mobility/endurance, fine motor skills and activities of daily living, speech/cognition and feeding. Each of these areas are treated by specific rehabilitation therapists: physical and occupational therapy, speech and language; and feeding. These interventions will be described later in the paper.Certain complications, comorbidities or secondary effects are related to heart failure and will affect the patient’s function:The most common cause of stroke in children is CHD or the treatment of CHD . AbnormaSome of the procedures used to support heart failure patients also have a high neurologic risk. A prospective cohort study revealed that 29% of patients on Berlin Heat have a at least one neurologic event, with most of them occurring within the first 2 weeks after implant . Major eThese neurologic events can affect their muscle tone, their mobility, use of upper extremities, participation in activities of daily living, feeding , speech Whilst relatively rare these can also happen in patients who undergo heart transplant and it can be related to positioning, ischemia and secondary effects of some of the transplant medication , 39. TheAs we have previously mentioned an important number of pediatric cardiac transplants are complex CHD patients. There has been extensive literature regarding neurodevelopmental delays in patients with CHD with abnormal executive function, cognitive and communication difficulties with widely implemented management guidelines . There aExercise capacity is decreased in patients with heart failure , includiPeak oxygen consumption, the gold standard for exercise capacity, has been showed to be related to morbidity and mortality in children with various forms of CHD –48 and iIn heart transplant patients this exercise limitation is mostly due to the cardiac autonomic denervation that can lead to chronotropic impairment  due to tSome of these limiting factors can improve with exercise training such as deconditioning and vascular function. Over the past few years there has been an increase in studies on exercise training in patients with CHD, many have shown improvement in exercise capacity , 55. ResDysphagia or feeding difficulties can entail difficulty with the oral preparatory phase of swallowing (chewing and preparing the food), the oral phase  and the pharyngeal phase . The different parts of the process can be affected in patients who undergo heart transplant and specially those who had a baseline CHD diagnosis . FeedingRisk factors for developing feeding difficulties in these patients include neonatal age , use of Complications of dysphagia have been shown to include aspiration leading to pneumonia, respiratory arrest, progressive chronic lung disease, malnutrition, increased risk of infection, prolonged length of stay in hospital, and increased risk of death , 69, 70.Communication and cognition can be affected due to multiple reasons in patients with heart failure and transplant. Some of the causes are shared with the feeding difficulties such as injury to the recurrent laryngeal nerve with vocal cord paralysis/palsy , prolongIn the acute hospital setting some patients may be non-verbal due to tracheostomy, mechanical ventilation and intubation . ProvidiThe goal of Rehabilitation is to enhance and restore functional ability and quality of life to those with physical impairments or disabilities that can be temporary or permanent. To do so a personalized program is developed depending on the needs of the specific patient.A Rehabilitation program can include medical management, use of rehabilitation equipment as well as the involvement of a variety of rehabilitation therapists that include physical, occupational, speech and feeding therapists.Recommendations for the different types of programs is based on recommendations from rehabilitation medicine, the cardiac surgical and medical teams, and the rehabilitation therapists both in the in- and outpatient settings.These programs and therapies can be provided in different settings:Outpatient clinics for patients prior to surgery or that have discharged home.Acute inpatient hospital setting for those patients admitted for medical or surgical management of their heart condition.Acute inpatient rehabilitation for patients with major functional impairments, who require ongoing acute medical management, intensive rehabilitation therapies, education for families, rehabilitation equipment evaluations and help with the supports at home and in the community.School and Early Intervention.Rehabilitation programs include the following critical components:Physical Therapists and Occupational Therapists play a vital role in the life of a child with heart failure. Children with heart failure are often referred to physical and occupational therapy for treatment of developmental delays . ChildrePhysical and occupational therapy evaluations begin with a thorough chart review to understand the child’s diagnosis, medical status and prognosis. The therapist will have an understanding of basic lab values and how this may impact evaluation and intervention as well as vital sign parameters for activity. The therapist should collect a developmental history from the patient and caregiver along with prior level of function, previous need for therapy services as well as home set up and caregiver support. It is also important to know if the child uses an assistive device or bracing at baseline.Children with heart failure often require physical therapy in a variety of settings to improve exercise capacity and endurance, progress gross motor skills, restore function and improve quality of life. Many children with heart failure may go on to be listed for heart transplantation, therefore physical therapy plays an important role to optimize the child’s endurance and function prior to heart transplantation. Physical therapists will conduct an examination, collaborate with patients and families to create goals and establish a plan of care for children with heart failure.The physical therapy examination will assess the child’s impairments, activity limitations and participation restrictions which will vary based on the child’s age, prior level of function and current medical status. The physical therapy examination may include assessment of muscle strength, joint range of motion, sensory and proprioceptive testing, coordination, balance, endurance, functional mobility, gross motor skills and developmental skills.The use of standardized assessments is recommended during a physical therapy examination in order to obtain a quantifiable measurement of a child’s baseline and enable measurable goals to be set. Repeat use of standardized assessments at re-evaluation will provide valuable data on the child’s progress. Infants and toddlers with heart failure often present with delayed attainment of gross motor milestones due to prolonged hospitalizations, previous surgeries, decreased strength and endurance. Children and adolescents with heart failure often present with decreased exercise capacity and may also present with strength, balance and coordination impairments due to pharmacological treatment causing neuropathies as well as sedentary lifestyle. Selection of a standardized assessment is made based on the child’s age and specific areas of impairment or skills that have been identified as areas of concerns by parents and providers.The 6 min walk test is easily performed, widely available and a well-tolerated test for assessing the functional capacity of patients with heart failure in everyday practice . The 6-mFor quality-of-life assessments the PedsQL and CHQ-PF50 have been used in the pediatric cardiac population , 87.Following an evaluation, the physical therapist will synthesize the information gathered to create measurable goals with the patient and caregivers and establish a plan of care individualized for each child. Typical goals for infants and toddlers with heart failure are to progress gross motor skills. Goals for children and adolescents will vary widely based on evaluative findings but may include improving strength, balance, coordination, endurance and functional mobility.An individualized physical therapy plan of care is created for each child and frequency of services is established. Physical therapy intervention is especially important for children with heart failure awaiting heart transplantation. Adult literature has shown that physical rehabilitation can improve functional capacity and quality of life, decrease hospitalizations and improve mortality in adults with heart failure , 89. LitTherapeutic interventions may vary depending on the inpatient or outpatient setting and availability of resources. Interventions will include facilitation of gross motor skills, strength training, balance and coordination training and endurance training. The physical therapist will modify activity based on the child’s age, oftentimes incorporating age-appropriate play to help engage the child.Occupational therapists play an important role for patients with heart failure. Occupational therapists are clinicians trained to work with heart failure patients across the lifespan. Occupational therapists are able to optimize the quality of life and help restore function . The maiOccupational therapy evaluations will focus on a variety of performance skills and client factors including cognition, strength, ROM, coordination, development, balance, functional mobility and ability to participate in ADLs and play. An occupational therapist may complete of standardized and non-standardized tests as determined by the needs of the child and family, the identified impairments the setting in which the evaluation takes place. The use of standardized assessments assists in establishing a baseline of occupational performance which allows for objective measurement of progress after and during intervention.Following an evaluation, the occupational therapist will develop an individualized plan of care that includes measurable goals that are developed with the patient and caregivers. Typical goals for infants and toddlers with heart failure are to progress their developmental skills and provide education to the caregivers for carryover. Goals for children and adolescents will vary widely based on the findings but may include improving functional strength and endurance, coordination, cognitive retraining, visual motor skills, energy conservation techniques, modifications for activities of daily living skills and coping strategies. Occupational therapy interventions support patient’s recovery and provide direct therapy to overcome any barriers that prevent them from participating in their occupations.In some instances, children with heart failure may require advanced support and implantation of ventricular assist devices. Post surgically, physical therapists and occupational therapists play a role in early mobility and restoring function. Postoperative precautions may be present following implantation of ventricular assist devices including sternal precautions, presence of multiple lines and tubes and vital sign parameters. Communication with the medical team is vital to determine timing of early mobility, specific precautions and vital sign parameters particularly during mobility and ADLs. Additionally, therapists play an important role in educating patients and families about postoperative precautions and adjustment to daily activity with their new device. This often includes education on sternal precautions, drive line precautions, connecting the VAD to battery power, and donning and doffing their VAD carrying device. As discussed above, there is also a high risk of neurologic complications associated with ventricular assist devices. Physical therapists and occupational therapists will be vital in assessing for neurologic compromise and treating impairments, activity limitations and participation restrictions to restore function post operatively. Following the immediate post-operative period, physical therapy is often indicated for continued strength and endurance training in preparation for heart transplantation. Occupational therapy is vital to address orthotic and/or rehabilitation assistive devices as well as adaptations to complete ADLs and engage in play based and school activities while inpatient. For the neurodevelopmental population, optimizing gross and fine motor skills prior to transplant is the focus of physical and occupational therapy. This often involves creative strategies and adaptations to activities to accommodate the patient’s VAD and maintain safety and precautions.In adults, there is evidence of improved exercise capacity after cardiac rehabilitation in patients following heart transplantation . In adulHowever, in pediatrics evidence regarding the effects of cardiac rehabilitation programs is growing but has shown promising results . EvidencWe would like to highlight that exercise training in pediatric patients with heart failure or transplantation might take place years after their surgery, due to their ability to participate in formal exercise testing and a structured exercise program. This is different to adults who normally receive cardiac rehabilitation after a surgical intervention.Based on literature mostly focused on CHD and adults, as well as clinical experience we would recommend the following program:A cardiopulmonary exercise test (CPET) prior to the program is recommended to better understand the factors contributing to a lower exercise capacity. A CPET will also help ensure the safety of initiating a rehabilitation program and help structure the exercise training component. Post-program it can help quantify the impact of the program.The patient will be provided with an individualized exercise prescription based on the CPET, diagnostic testing, comorbidities and goals of the patient. This prescription will follow the FITT principle of exercise frequency, intensity, time, type, volume and progression.Centered based programs last ~12 weeks, with ideally two supervised exercise sessions per week. The program should be over seen by a medical provider. Some of the studies have been homebased.Aerobic training: should be the main component of the program. Intensity can be established by the Borg Scale, the Talk test and the heart rate reserve. However, the heart rate reserve might not be applicable to the heart transplant patients.Resistance training: include exercises with low resistance and a high number of repetitions.Warm up and cool down exercises.Education: regarding cardiac diagnosis, CV risk factors, physical activity and nutrition.Vitals SignsBlood pressure, oxygen saturation and heart rate should be taken before and after the program.TelemetryDepending on clinical recommendations.Initiate further assessment of the patient if symptoms such as dizziness especially if accompanied by drop in BP, concerning arrhythmias, or chest pain or dyspnea felt to be cardiac in nature appear.If on Telemetry: Exercise to be stopped if patient has clinically significant STT wave changes, sustained ventricular tachycardia, high grade ectopy or AV block.Patients with VAD and recovering from heart transplant are at significant risk of dysphagia (as described above) and timely assessment of feeding skills and swallow function is crucial. A speech-language pathologist (SLP) specializing in feeding and swallowing should conduct a clinical assessment of feeding and swallowing should as soon as the patient is deemed clinically ready to consider oral feeding. In determining readiness for assessment, the patient’s tolerance of enteral feeds, degree of respiratory support and level of alertness should be considered. In general, patients should demonstrate adequate tolerance of gastric feeds prior to initiation of oral feeds as feeding intolerance may impact both the desire to eat, as well as the safety. Given increased risk of aspiration while on NIPPV  and postClinical assessment of feeding and swallowing should consist of thorough history gathering including baseline feeding difficulties, risk factors for dysphagia, assessment of state and baseline status, oral mechanism examination, assessment of vocal quality, assessment of non-nutritive suck and oral reflexes in infants, all prior to offering any oral trials. When offering oral trials, clinicians should proceed slowly and with caution. In infants, a very slow flow nipple should be utilized, in particular if risk factors for aspiration from above have been identified. In older children, oral trials should begin with ice chips or water via teaspoon, proceeding to larger bolus size and consecutive swallows dependent on if the patient is demonstrating any overt signs of aspiration or signs of stress. Depending on state and degree of deconditioning, small volume trials of purees and developmentally appropriate solid foods can also be considered. When offering solid foods, chewing skills, ability to fully pulverize solids prior to swallowing and oral clearance should be considered in determining safety for solids and choking risk. Oral trials should be discontinued at any point where the patient is demonstrating overt signs or aspiration or physiologic instability.The primary focus of a clinical feeding and swallowing evaluation should be on safety to proceed with oral trials, including safe oral diet recommendation and need for further instrumental assessment of swallow function. Additionally, a patient’s interest in oral feeding and developmental feeding skills should be taken into consideration. Patients should not be pushed to participate in assessment if they are resistant, nor if they are not alert enough to actively engage.Many patients following heart transplantation will require instrumental assessment of swallow function. Instrumental assessment of swallow function should be considered if there are overt signs of aspiration on clinical assessment, or if the patient is considered at high risk of aspiration based on history, in particular patients with neurologic insult , 104 or Management of dysphagia in pediatric patients with VAD or following heart transplant will occur based on findings from clinical and instrumental assessments of feeding and swallowing. In patients found to aspirate on instrumental assessment, strategies to improve airway protection from above should be trialed during the instrumental assessment to determine safety and improvement. These strategies may include altering positioning, altering method of delivery of liquids , pacing bottle feeding or adjusting bite size or food consistency, and thickening liquids. Decisions regarding use of thickened liquids should be guided by instrumental assessment of swallow function whenever possible. Given increased incidence of silent aspiration in patients with vocal fold immobility or neurologic insult, as well as challenges with thickening liquids in the pediatric population as a whole , use of Once a patient’s swallowing safety has been established via clinical and instrumental assessment as appropriate, while inpatient, feeding therapy should be provided with goals of monitoring safety with oral feeds, and advancing oral intake as tolerated. Clinicians should be closely monitoring swallow function and signs of aspiration with oral trials, and making adjustments to positioning, delivery method and diet recommendations as appropriate. In addition, goals such as reducing oral hypersensitivity and improving tolerance of oral stimulation, as well as improving oral motor skills for feeding can be addressed. In young patients who are deemed unsafe for oral feeding, a plan for oral stimulation should be provided to avoid development or worsening of oral aversion, as well as to promote ongoing advancement of oral motor skills for feeding. Oral stimulation should be developmentally appropriate and may include use of pacifier, safe teething toys, familiarization with feeding utensils and therapeutic tastes. Principles of motor learning should be kept in mind when treating both infants who are learning to swallow and in retraining swallowing with older children . Parent Need for supplemental nutrition should be closely monitored to ensure that opportunities for oral intake are maximized as is safe, while nutrition and hydration needs are met . Most paThus, far there has been limited research regarding the incidence and risk factors for dysphagia in patients with VAD and following heart transplantation, and further study is indicated. Further research regarding efficacy of strategies used to treat dysphagia in this population are warranted. Long-term feeding outcomes for patients who undergo early heart transplantation should also be followed.Children with heart failure may present with a broad spectrum of speech, language, and communication needs. Given potential baseline speech and language delays for patients with congenital heart disease , 116, heTo best support speech, language, and communication in children with heart failure, the SLP may perform an initial assessment or screening tailored to each child’s individual needs, age, medical status, setting, and situation. Assessment may include clinical observation, parent interview, language sampling, standardized testing, or criterion referenced measures. Given potential for risk of communication impairment in children with heart failure across a variety of domains, initial screening or assessment should include information gathering and direct observation regarding hearing and vision status, vocal cord function, language comprehension, social-emotional functioning, articulation, language production, literacy, cognition, sensory skills and needs, and motor profile. An oral mechanism exam should also be conducted. Following screening or assessment, the SLP will work with patients and families to determine individualized goals of care. Treatment recommendations may change depending on the child’s medical status, setting, and areas of need.In many instances, children with heart failure experience prolonged hospitalizations due to medical complexity, surgical interventions, VAD placement, or while awaiting heart transplant. For patients with baseline speech and language impairments prior to their hospitalization, carryover of intervention in the acute care environment may be warranted to support development of skills and to prevent regression, particularly in the context of a prolonged admission. For children with acute changes in their speech, language, or communication profile, early intervention in the acute care setting is critical to support communication access, early rehabilitation, and ongoing monitoring of clinical status. As many children with heart failure have extended hospital stays while waiting for transplant, possibly following an acute neurological event, vocal cord injury, or sensory impairment , their access to rehabilitation outside of the acute hospital setting can be limited. Therefore, targeted intervention to support speech, language, and cognitive communication should be implemented early for optimal outcomes.Patients with heart failure may experience acute functional communication difficulties or a non-speaking status secondary to new communication impairments , or due to baseline communication impairments. This inability to functionally communicate puts patients at heightened risk of sentinel and adverse events, increased length of stay, and can impact psychological well-being . RegardiFor ongoing speech, language, and communication needs following heart transplant or discharge from the acute care setting, continued intervention may be warranted to support functional communication, academic participation, social experiences, and improve quality of life. Ongoing interventions and recommendations should be highly individualized to each child’s specific needs based on findings from comprehensive and dynamic assessment. Goals may be supportive in targeting areas of need across a variety of communicative domains, including expressive and receptive language, articulation, voice and resonance, cognitive communication, literacy, and pragmatics. For children who cannot functionally access spoken language, implementation of AAC tools and strategies may be required for ongoing communication access needs. Treatment goals and recommendations, including areas targeted and frequency of intervention, may change over time to meet evolving needs. Changes in health status may also impact treatment approaches or recommendations within this population.The acute care setting often poses challenges when completing evaluations and providing direct interventions for all rehabilitation therapists. These challenges are not limited to medical instability, limits within the physical setting and time constraints due to multiple medical providers and treatments. Patients with heart failure are often attached to various medical machines, lines and tubes that may require additional staff for safety and monitoring of hemodynamic status during mobility, ADLs, feeding and complicating communication. Many medications used to treat heart failure may impact patients’ level of arousal and ability to cognitively participate in their therapy sessions. Infants often required prolonged hospitalizations during critical periods of development. There is a challenge in the acute care setting to normalize an infant’s environment in a way that allows for them to progress their developmental milestones. Children and adolescents who require prolonged hospitalizations have interruptions in their daily routines and it is difficult to simulate day to day activities and routines within the acute care environment.There is limited research in the pediatric setting on appropriate exercise guidelines and vital sign parameters particularly for children with very low ejection fraction. Additionally, children with heart failure often exhibit growth failure due to high metabolic demands and increased energy expenditure, which can lead to failure to thrive and further medical complications . DiscussSurvival has increased in children with heart failure, including those necessitating heart transplantations, due to advances in medical and surgical management. However, quality of life and function might be compromised due to the comorbidities and complications of heart failure and its treatment.It is essential to provide heart failure patients with individualized multidisciplinary rehabilitation interventions both in the in- and outpatient settings to optimize their function and quality of life.AU contributed to conception and design and writing of the paper. EB, EL, KE, MS, and PE wrote sections of the manuscript. PE overviewed the paper. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We report a rare case of a 43-year-old woman with calcific annular constrictive pericarditis (CP) encircling the basal segment of the right ventricle and the mid-segment of the left ventricle (LV) lateral wall. Over time, localized calcification has caused LV to be tightly strangled and shaped like a gourd. However, multimodality imaging confirmed no significantly clinical constriction associated with decreased cardiac movement and function. Additionally, cardiac magnetic resonance feature tracking confirmed the relatively preserved diastolic function and the characteristic “plateau” pattern of CP. The treatment strategy of this case is challenging and dialectical. The inelastic pericardium inhibits cardiac filling, causing cardiac diastolic filling dysfunction and diastolic heart failure . CP diagin situ –8. Here,A 43-year-old woman was referred to Anzhen Hospital  for a definite diagnosis and diastolic function evaluation. With a 7-year history of discovering pericardial calcification, she had no obvious symptoms or signs of systemic congestion and heart failure, only intermittent mild edema of both lower limbs. Laboratory examination showed that she had normal inflammatory marker levels, liver and renal function levels and plasma B-type natriuretic peptide level, and laboratory examination also excluded tuberculosis and rheumatism. Electrocardiogram showed sinus rhythm and secondary ST-segment and T-wave changes caused by pericardial calcification, and chest radiogram demonstrated pericardial calcification was not observed obviously . TransthTo provide a more accurate assessment of myocardial deformation and LV diastolic function, we performed cardiac magnetic resonance feature tracking (CMR-FT) strain rate analysis for this patient. We analyzed LV global myocardial strain rate and LV global and regional basal-mid-apical segment time-strain curves, and obtained a three-dimensional LV feature tracking model. CMR-FT analysis indicated that the peak global longitudinal strain (GLS) was −11.9%, the peak global circumferential strain (GCS) was −19.1%, and the peak global radial strain (GRS) was 32.3%. Additionally, the characteristic “plateau” pattern of CP could be observed in LV global and regional mid-segment time-strain curves . In addiThe uniqueness of this case is that calcified annular constrictive pericarditis is an extremely rare form of localized constrictive pericarditis. More precisely, the calcification, in this case, surrounds the right atrioventricular groove and the mid-segment of the LV lateral wall, rather than typically encircling the bilateral atrioventricular groove as reported by Carabelli et al. . GradualOn the other hand, multimodality imaging evaluation of this patient confirmed that LVEF and myocardial movement were not significantly reduced, and no evidence of necrosis or fibrosis was observed in the myocardium. Through CMR-FT strain rate analysis, we found that LV global strain rate of the patient demonstrated the relatively preserved diastolic function . For most cases of CP, during the process of diastolic filling, LV stiffness and pericardial restraint will lead to increased LV afterload and impaired motor function, which ultimately leads to a significant reduction in circumferential deformation . However, due to the relatively preserved myocardial motion and function, this patient did not have a significant decrease in global strain rate. In addition, the characteristic “plateau” pattern of CP in LV global and regional mid-segment time-strain curves corresponded to the location of calcified pericardium . The patients/participants provided their written informed consent to participate in this study.JD was the guarantors of the integrity of the entire study. HW and QL are responsible for the study concepts and design. ZY prepared the first draft of the manuscript, which was critically revised by XD, JZ, and JD. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (Grant No. 82170381).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Each underwent 2-dimensional (2D) imaging echocardiography, Doppler, tissue Doppler imaging echocardiography, and speckle-tracking echocardiography (STE) for comparison of cardiovascular structure and function parameters. Compared to the young mice, the old had significantly higher body weight (BW), and lower diastolic and mean arterial pressure. The left ventricular (LV) end-diastolic and end-systolic volumes, and left ventricular mass, were significantly higher in the old mice. Within each sex, the cardiac diastolic and systolic function parameters were comparable between the young and old. Isovolumetric relaxation time (IVRT)/diastolic time interval (DT) and the maximum drop rate of pressure in LV (− dP/dtmax) were significantly lower in the old mice, while the LV relaxation time constant (Tau) was significantly higher. Spearman’s rank correlation showed a positive association between IVRT/DT and − dp/dtmax . Among the males, the maximum rise rate of pressure in LV (+ dp/dtmax), and systolic global longitudinal strains and rates  were significantly different between the young and old. Spearman’s rank correlation showed positive association between S-GLS, S-GLSR and + dp/dtmax (r = 0.709 and r = 0.499). Regarding vascular structure, the ascending aorta systolic and diastolic diameters were significantly higher in the old mice compared with the young. The male mice had progressive, age-related aortic stiffness. Ageing in mice leads to changes in cardiovascular structure and cardiac diastolic function, but systolic function is relatively well preserved in females. Changes in cardiac function and arterial stiffness were more significant in males than females. Traditional ECG is better than STE for evaluating LV diastolic function; STE is better for LV systolic function.This study employed traditional and advanced echocardiographic techniques to assess comprehensively age- and sex-related changes in cardiovascular structure and function in wildtype (WT) mice. Forty-five normal adult wildtype mice were apportioned to groups based on age and sex: 2-month (young) male or female, and 24-month (old) male or female ( Epidemiological studies4 have shown that arterial stiffness and hypertension, and related cardiovascular diseases such as stroke and myocardial infarction, are more prevalent in the aged than the young. Strait et al.5 showed that impairment of cardiac diastolic function occurs with aging, but systolic function is preserved.In humans, the heart and blood vessels undergo changes in structure and function (SF) with advancing age that lead to the development of various diseases6.Age-associated changes in cardiovascular SF may be monitored using the current echocardiographic (ECG) techniques. Mice have a naturally short lifespan, which makes the mouse a particularly interesting model for longitudinal studies. Mice age more quickly than humans do, and a mouse at 24 months of age is equivalent to a human in his seventh decade, according to the probability of survival curves generated by the National Institutes on Aging7. Yet, there is little comprehensive study about age- and sex-related changes in mice with regard to cardiovascular SF. The present study employed traditional echocardiography and advanced ECG techniques, comparing with gold standard for evaluating cardiovascular function, to assess comprehensively the age- and sex-related changes in cardiovascular SF in WT mice.Recent advances in imaging technology, with improved resolution, have made ECG in mice and rats a valuable and generally well-accepted tool for understanding the physiological and pathophysiological changes associated with ageing and cardiovascular diseasesn = 13); 24-month-old male (n = 13); 2-month-old female (n = 13); and 24-month-old female (n = 6). The 2- and 24-month-old mice were considered young and old, respectively.Forty-five normal adult WT mice were apportioned into 4 groups according to age and sex: 2-month-old male . The animal care and experimental protocols were approved by the University of Pennsylvania Committee on Animal Care. The study was carried out in compliance with the ARRIVE guidelines.2 mask inhalation. After shaving and removing the hair on the neck, chest, and abdomen with depilatory cream, the mice were placed supine on a controlled heating pad. The body temperature was maintained at 37 °C and electrocardiogram limb electrodes were placed. The heart rate (HR), respiration frequency, and body temperature were continuously monitored. All ECG measurements were the average of 3 cardiac cycles. The acquired data are detailed below.A high-frequency ultrasound device  was used for ultrasound imaging. We used two types of linear array probes, MS-250S (frequency 13–24 MHz) and MS-550D (frequency 22–55 MHz). The MS-250S probe was mainly used to measure the heart function of mice, and MS-550D was mainly focused on measure the vascular function of mice. All mice were measured for BW before the operation. During the procedure, the mice were anesthetized with 2–3% isoflurane in an induction chamber and maintained with 1.0–1.5% isoflurane delivered via 100% O8 was used to calculate LV mass and relative wall thickness (RWT), which were derived using the following formulas: LV mass, g = 1.053([LVIDd + IVSd + LVPWd]3 − [LVIDd]3), and RWT = (IVSd + LVPWd)/LVIDd.The following were measured from the LV mid-papillary level in the parasternal short-axis view with 2D M-mode imaging Fig. A: intervDoppler measurements of the mitral valve inflow velocities were recorded from an apical 4-chamber view, with a cursor positioned by the tips of the mitral valve leaflets. Diastolic function was evaluated from measurements of the early filling velocity (E) and the atrial filling velocity (A), and calculation of the E/A ratio. The following values were measured using mitral valve spectral Doppler Fig. B: isovolSpeckle tracking-based strain analysis of 3 consecutive cardiac cycles 2D gray scale ECG images were acquired from the parasternal long- and short-axes using the Vevostrain software package . Semi-automated tracings were performed on the endocardial and epicardial borders, which were then corrected as needed to achieve good quality tracking throughout each cine loop. Strain measurements were performed by processing the tracked images in a frame-by-frame manner, and were averaged from the acquired cardiac cycles, from which curvilinear strain and strain rate data were obtained. Each of the LV myocardium long- and short-axis views was divided by Vevo Software into 6 standard anatomic segments.Analyses of the following were performed from parasternal long-axis views Fig. A,B: systThe probe was placed vertically in the mouse neck, slightly left, to show clearly the ascending aortic lumen and aortic valve (AV) by adjusting the position of the probe. The ascending aorta diameters at end-systole and end-diastole  were measured in M-mode imaging Fig. D. The raThe distance between the carotid and iliac arteries was measured in millimeters with Vernier calipers, defined as the difference between the distance from the iliac to the nose hood, and the distance from the ascending aorta to the nose hood. The pulse-transit time from the ascending aorta to the iliac arteries was obtained by subtracting the time intervals of the mean right-ascending aorta from the mean right-iliac foot. The pulse wave velocity (PWV) was calculated as the distance between the carotid and iliac arteries divided by the pulse-transit time.Invasive cardiac catheter measurements of cardiovascular function were performed at the end of study. Under anesthesia with tribromoethanol , and/or 1–2% isoflurane, each mouse was placed on a heating pad to maintain body temperature. The responsiveness of the mouse was tested by toe pinching. If the animal responded, additional anesthesia was administered. The surgical areas were shaved and antiseptic agents (betadine and 70% ethanol) were applied. The mouse was secured to the operating field with surgical tape. A blunt dissection was performed over the thin muscle layer around the throat, and the right carotid artery was exposed and isolated. The suture around the distal end of the artery was secured. A suture was then placed loosely around the proximal end of the artery, on which a small metal hemostat clip was placed to minimize bleeding during catheter insertion. After making a tiny incision near the distal end of the artery with micro-scissors, a pressure or pressure–volume loop catheter (1F or 1.4F) was gently inserted into the artery while the catheter tip was quickly advanced down the ascending aorta via the aortic valve into the left ventricle. The proximal suture was tightened to minimize blood loss.The pressure or pressure–volume loop data was collected and cardiovascular intervention  was performed. To measure the pressure gradient over the aortic-banded region, another pressure catheter was inserted via the abdominal artery or femoral artery. Before and after isoproterenol (or dobutamine) dosing , the following hemodynamic data were recorded: The peak systolic and diastolic pressures ; mean arterial pressure (MAP); Tau; + dp/dtmax and − dp/dtmax.t-test was used to compare the data between groups of the same sex. Spearman’s rank correlation test was used to assess a correlation between parameters. Probability (P) values < 0.05 and < 0.01 were considered significant and very significant, respectively.All echo data were analyzed offline by a single trained observer. SPSS 20.0  was used for all analyses. All measurements are shown as mean ± standard error of at least 3 independent assays, unless otherwise noted. The independent samples P < 0.01). Within sex, the young and old mice were comparable with regard to HR. The SP of the old females was very significantly lower than that of young females (P < 0.01), but between the young and old males the SP were comparable . Between the young and old females, the LV mass/BW, RWT, and SV of the old females were significantly higher than that of the young females (P < 0.05), but between the young and old males, these parameters were comparable  of the old groups were significantly higher compared with that of the young. Concerning vascular functional parameters, compared with the young males, the ∆AADR of the old males were significantly lower, and the PWV were significantly higher. Between the female groups, the ∆AADR and PWV were similar Fig. .Figure 89. Murine animals are very similar to humans in terms of genome, cardiovascular anatomy, and physiology10. STE has been widely used in clinical cardiovascular disease, and is a quantitative, rapid, and accurate method to evaluate left and right ventricular function12. Greenberg et al.13 reported the mean rate of strain as an index to evaluate LV systolic function. De Lucia and co-workers14 are one of the groups that have published age-related changes in cardiac systolic and diastolic function using conventional ECG and STE in a mouse model. They reported that, compared with conventional ECG, STE reflects subtle changes in LV global/regional strain, relaxation, and synchronicity at earlier stages of aging. In the present study, we not only used conventional ECG parameters, but also STE to evaluate LV diastolic and systolic function in mice. Thus, we obtained data for a wide range of parameters and evaluated changes in heart function more comprehensively and accurately.The process of aging is evolutionarily conserved and yet poorly understood. Cardiovascular disease accounts for more than 30% of global deaths, and heart failure is the leading cause of death for persons older than 65 years. The age-associated changes in cardiovascular SF may well be reflected by the occurrence, severity, and prognosis of cardiovascular disease15. In the present study, because of the fast heart rate of mice, we could not readily identify the E and A in most of these animals, and therefore only recorded the E. We found that 24-month-old mice exhibited obvious structural changes and modest declines in diastolic function compared with the 2-month-old mice. Important factors that contribute to abnormal diastolic function with normal aging include greater cardiomyocyte size, higher rates of apoptosis with lower myocyte numbers, increased collagen deposition, and functional changes at the cellular level16. These changes may result in greater LV diastolic stiffness with aging17. At present, the gold standard for evaluating LV diastolic function is the constant Tau and − dP/dtmax, which are measured by cardiac catheterization18. Compared with the gold standard, we found that IVRT/DT was the most sensitive parameter to reflect LV diastolic function, as determined by ECG. STE was no better than the conventional ECG for evaluating LV diastolic function in mice. Our study also found that the e/a ratio was significantly lower in the old male mice, relative to the young males. It is possible that the old males had impaired LV relaxation, with a mild-to-moderate decrease in LV compliance, and a decline in diastolic function that was more obvious in males compared with females of the same advanced age.Normal cardiac aging is characterized by changes in SF. In conventional ECG, the evaluation of LV diastolic function employs the E, A, E/A ratio, IVRT, DT, IVRT/DT and TDI values 19. LV SF in mice has been assessed by M-mode echocardiography. Nonetheless, as M-mode-derived volume and mass calculations are based on measurements on a single plane, they may be susceptible to error. We found that the LV systolic function parameters , measured via traditional ECG, were not significantly different among the age and sex groups. But after applying STE, it was found that S-GLS and S-GLSR of the old males was significantly higher than that of the young males, and S-RLS and S-RLSR showed obvious difference mainly in apex. Among the females, S-GLS and S-GLSR were similar. These values were consistent with the gold standard value (+ dp/dtmax) of LV systolic function. Therefore, LV systolic function was relatively well preserved even as age advanced in the female mice. These results are consistent with the Koch et al.20 study, in which there an age-dependent decrease in several systolic and diastolic function parameters was determined in the male mice, but not the females.LVEF and FS% are the main parameters to evaluate LV systolic function when using conventional ECG. However, conventional ECG techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice21. Classically, PWV can be determined from the difference (or delay) in propagation of arterial pressure waves (or flow) between two recording sites in the line of pulse travel. PWV is closely associated with the intrinsic elasticity of the arterial wall and has been considered the gold standard measure of arterial stiffness22. Arterial stiffening increases with age, resulting in an increase in PWV. A decrease in arterial elasticity, and thus an increase of stiffness of the central elastic arteries such as the aorta, is a powerful independent predictor of cardiovascular diseases, mortality, and morbidity23. Our data showed that male mice had progressive, age-related declines in aortic structure and increased aortic stiffness reflected by the ∆AADR and PWV. Female mice had only age-related changes in aortic structure, and there was no significant change in aortic function. It may be that arterial stiffness in mice develops at an earlier age males than in females. The processes by which arterial stiffness increases with age are uncertain, some scholars have found that arterial stiffness was related to collagen fibrosis deposition24. There has been growing interest in identifying and understanding the genetics and underlying mechanisms25.Arterial stiffness is an independent predictor of cardiovascular outcomes, such as myocardial infarction, cognitive decline in aging, stroke, and kidney diseasesWe acknowledge several limitations in this study. First, the population of old females was small, and to confirm these results a larger population is required. Second, the cardiovascular function of the mice was tested only in the resting state, without considering reserve function. Finally, currently 2D STE must be analyzed off-line based on a clear 2D ultrasonic image, which cannot be analyzed in real time.Our data suggest that ageing in mice leads to changes in cardiovascular structure and cardiac diastolic function, but systolic function is relatively well preserved in females. Changes in cardiac function and arterial stiffness in male mice may occur at a younger age than in females, or are more obvious. This may be because in aging female mice, changes in cardiovascular structure are more conducive to the maintenance of functions. Finally, in mice STE is not as sensitive as traditional ECG for evaluating LV diastolic function, but it is better than traditional ECG for evaluating LV systolic function.