LV-GLS had the strongest association with PALS at multivariable analysis . Among HF stages, LV-GLS remained the most important PALS predictor (p < 0.0001) whereas age was only associated with PALS in lower HF-stage 0/A or B . LA volume increased its association to PALS moving from stage 0/A  to C . PALS was the single most potent echocardiographic parameter in predicting the HF stage . PALS remained independently associated with HF stages after adjusting for ejection fraction, E/e′ ratio, and mitral regurgitation grade (p < 0.0001). Although influenced by LV-GLS and LA size across HF stages, PALS is incrementally and independently associated with clinical status. LA function may reflect a substantial part of the hemodynamic consequences of ventricular dysfunction.Few studies analyzed left atrial (LA) peak atrial longitudinal strain (PALS) determinants, particularly across heart failure (HF) stages. We aimed to analyze the pathophysiological and clinical PALS correlates in a large multicentric prospective study. This is a multicenter prospective observational study enrolling 745 patients with HF stages. Data included PALS and left ventricular global longitudinal strain (LV-GLS). Exclusion criteria were: valvular prosthesis; atrial fibrillation; cardiac transplantation; poor acoustic window. Median global PALS was 17% [24–32]. 29% of patients were in HF-stage 0/A, 35% in stage-B, and 36% in stage-C. Together with age, the echocardiographic determinants of PALS were LA volume and LV-GLS (overall model RThe online version contains supplementary material available at 10.1007/s10554-022-02669-x. Left atrial (LA) peak longitudinal strain (PALS) can be easily obtained by speckle tracking echocardiography (STE) and reliably reflects the LA phasic function . PALS haThe LA function mirrors the elevation of left ventricular (LV) filling pressure , is inflThe present study aims to analyze PALS pathophysiological and clinical correlates in a large multicentric prospective study, including comprehensively characterized HF patients from stage 0 to C.From July to October 2018, the european association of cardiovascular imaging (EACVI) heart imagers of tomorrow (HIT) Members and/or Ambassadors experienced in echocardiography, who agreed to participate, were asked to collect clinical and echocardiographic data in various HF stages. The complete protocol of the original study is reported elsewhere . BrieflyA complete clinical evaluation was performed at the time of the enrollment including a comprehensive cardiovascular risk factor assessment and evaluation of major comorbidities. Each echocardiogram was performed using a high-quality machine equipped with a 1.5- and 3.6-MHz transducer. The LV and LA volumes were assessed from apical four- and two-chamber views using the biplane modified Simpson’s rule, according to current recommendations . The LV A frame rate of 40–80 fps was required for the STE measurements, and images were analyzed by semi-automatic software . Two different echocardiographers, blinded to each other, performed the measurements in each center. A predefined approach was adopted by all centers for LA strain measurements . PALS waLV strain quantification was assessed by an endocardial point-and-click approach, the ROI was manually defined and eventually modified, in each apical view . A total of 18 segments were obtained, six for each view, and GLS reported , or numbers and percentages  as appropriate. Comparisons across patient groups were performed using analysis of variance (ANOVA followed by the post hoc Bonferroni test for multiple comparisons), Wilcoxon test, or Chi-squared test. PALS determinants were selected according to their univariable association with PALS and physiological plausibility. Subsequently, to identify the parameters with an independent association to PALS, a multiple linear regression analysis was performed (using PALS as a continuous dependent variable) as well as logistic regression analysis . To further validate the results, a neural network  model was applied.PALS clinical significance was tested with multinomial logistic regression analysis using HF stages  or NYHA class (I vs. ≥ II) as the dependent variables; the area under the curve (AUC) is reported. All analyses were performed using JMP®, Version 14. SAS Institute Inc., Cary, NC. The significance level was set at 0.05 for all analyses.A total of 745 with complete clinical and echocardiographic evaluation formed the study cohort. Clinical and echocardiographic characteristics are presented in Table 2 = 0.50, p < 0.0001) as well as for PALS above the cohort median value, using a neural network to validate the prediction provided similar results .The major echocardiographic features associated with PALS were age , LAVI , and LV GLS  Fig. . Univari2 grew from 0.50 to 0.51). Therefore E/e′ was not included in the final model. Interestingly, no meaningful association was noted between PALS and diastolic blood pressure or heart rate; a complete list of PALS echocardiographic correlates is presented in Supplementary Table 1. Repeating the analysis using the advanced echocardiographic measurements did not affect the results .At the univariable analysis, E/e′ was significantly associated with PALS . However, adding E/e′ to the other determinants in a nested regression model did not significantly increase the PALS prediction . Among the 268 patients in HF stage C, 67 (25%) had ischemic etiology, 85 (32%) related to systemic hypertension, 67 (25%) to valvular heart disease, and the remaining 49 (18%) were labeled as non-ischemic or mixed etiology. Interestingly, there was no interaction between the HF etiology and the PALS-LV GLS relationship (p for interaction = 0.6).The relative importance of each PALS determinant was analyzed according to the HF stages as illustrated in Fig. Multiple echocardiographic features characterized the HF stages  patients were symptomatic (NYHA class ≥ 2) at the time of echocardiographic examination. PALS was significantly associated with symptomatic status in a multivariable model including his determinants , and even after adjustment for LV ejection fraction, mitral regurgitation grade and E/e′ ratio .The PALS value is mostly influenced by age, LA size, and LV GLS.The LV GLS is the strongest determinant of PALS; of note concomitant preserved PALS and reduced LV GLS is rare.PALS is related to age among patients with HF stage 0/A or B, whereas the LA size is more important in more advanced HF stages (B and C).Despite its multiple determinants, PALS is the superior echocardiographic parameter for characterization of the HF stages and for predicting the presence of symptoms.The present study, taking advantage of a unique large multicentric prospective cohort, demonstrates that:Growing evidence is accumulating on the clinical importance of the LA function—mostly measured by PALS—in all HF stages, particularly stages A and B which are characterized by early LV and LA remodeling. Indeed, LA mechanics reflect the degree of functional and morphological chamber adaptation better than the conventional echocardiographic parameters. As a paradigmatic example, patients with hypertension and diabetes have shown an early reduction of all LA myocardial deformation components even in the presence of normal LA size . FurtherThe present study is one of the largest cohorts, specifically addressing PALS correlates, and even more important the first study to analyze differences in atrial function across multiple HF stages. There are a multitude of physiological features associated with PALS , but onlThe present study’s relatively large sample size and the wide range of explored atrial and ventricular strain values enlighten details of the PALS-GLS relationship. Indeed, the association between the two advanced echocardiographic measurements is not strictly linear, and it is rare to present with reduced GLS but preserved PALS. This aspect agrees with the potential anticipatory nature of reduced PALS towards a GLS reduction and reveals that low GLS almost invariably relates to low PALS. In other words, in patients with relatively preserved LV GLS, PALS value mostly reflects intrinsic atrial properties and holds its distinctive pathohistological role ; with a Another novel result of the present study is that HF-stage influences the age-PALS relationship. Age seems a significant determinant of atrial stiffness in patients with no or limited cardiac involvement; however, in more advanced HF stages (B and C), different hemodynamic or biochemical drives increase LA stiffness, which becomes age-independent in HF-stage C. It is to be acknowledged that patients in HF stage B and C are older than those in stage 0/A, but the age-PALS correlation progressively decreases with the HF stage despite the similar age in stages B and C. This supports the change in determinants rather than the age ranges as a possible explanation for the significant interaction.LA volume showed an independent association with PALS, which increased in strength moving from HF stage 0/A to C. The explanations for this behavior reside in the multiple pathophysiological meaning of LA size, which reflects the elevation of diastolic filling pressure over time , 24, theThe lack of follow-up is the main limitation of the study; however, the present study provides contemporary insights into PALS’ clinical meaning. Indeed, this atrial parameter was the most characterizing echocardiographic parameter of HF-stage, which is mostly a clinically defined stage, and it is not based on LA chamber characteristics or any of the PALS determinants. In invasive studies conducted in advanced HF, LA strain was the best determinant of pulmonary capillary wedge pressure among the echocardiographic features . This waIn this prospective large multicenter study LV function by GLS, LA size, and age are independently associated with PALS with hierarchical importance influenced by patients’ HF stage. LA strain is a crucial HF stage characterizing feature and strongly relates to the presence of symptoms.Supplementary file1 (DOCX 914 kb)Below is the link to the electronic supplementary material.


Deformation imaging represents a method of measuring myocardial function, including global longitudinal strain (GLS), peak atrial longitudinal strain (PALS) and radial strain. This study aimed to assess subclinical improvements in left ventricular function in patients undergoing transcatheter aortic valve implantation (TAVI) by comparing GLS, PALS and radial strain pre and post procedure.We conducted a single site prospective observational study of 25 patients undergoing TAVI, comparing baseline and post-TAVI echocardiograms. Individual participants were assessed for differences in GLS, PALS and radial strain in addition to changes in left ventricular ejection fraction (LVEF) (%).Our results revealed a significant improvement in GLS  with no significant change in LVEF . There was a statistically significant improvement in radial strain pre and post TAVI . There was positive trend towards improvements in PALS pre and post TAVI .In patients undergoing TAVI, measuring GLS and radial strain provided statistically significant information regarding subclinical improvements in LV function, which may have prognostic implications. The incorporation of deformation imaging in addition to standard echocardiographic measurements may have an important role in guiding future management in patients undergoing TAVI and assessing response. Aortic stenosis (AS) is the commonest primary valvular abnormality necessitating surgical or percutaneous intervention in Europe and North America . The mosTransthoracic echocardiography (TTE) remains the gold standard investigation of choice for diagnosing and quantifying the severity of AS with several echocardiographic parameters being used. Historically, left ventricular ejection fraction (LVEF) % has been the most commonly used measure to determine LV systolic function. More recently however deformation imaging has become an important method of determining clinical and subclinical assessment of heart chamber function. Deformation imaging encompasses myocardial strain such as shortening, thickening and lengthening of myocardial fibres and includes global longitudinal strain (GLS), peak atrial longitudinal strain (PALS) and radial strain . GLS is Deformation imaging also allows us to assess left atrial function and also can assess the different phases of left ventricular filling dynamics. In the left atrial (LA) reservoir phase, as the LA fills and stretches, there is deformation called peak left atrial longitudinal strain (PALS), which peaks in systole at the end of LA filling, before the opening of the mitral valve, and is reflective of LV systolic function. Radial left ventricular strain represents the sum of both subepicardial and subendocardial radial deformations, as there are no radial myocyte fibres. Incorporating GLS, PALS and global radial strain (GRS), in addition to standard echocardiographic measurements, may be useful as a predictor of cardiovascular outcomes in patients post TAVI insertion.The primary aim of this study is to assess changes in GLS, PALS and GRS in patients pre and post-TAVI as predictors of subclinical improvements in LV function. Our secondary aim is to provide information for the development of future larger scale studies.This study was a single site prospective observational study in St. James Hospital, Dublin, Ireland. A total of 25 patients were included in the study. Patients were identified from hospital lists and from the hospital’s cardiology outpatient department. Pre-TAVI echocardiograms were performed as routine work-up before valve implantation. Patients were recalled for out-patient review and echocardiogram examination approximately 6 weeks post-TAVI. Some patients did not have local follow-up and therefore were contacted to present for an out-patient echocardiogram approximately 6 weeks post-TAVI. There were 11 individuals with post-TAVI TTEs performed within 14 days of their procedure due to difficulty attending 6 week follow-up. The mean (SD) interval before pre-TAVI TTE was 25.84 (28.2) days; median = 16  days. The mean (SD) interval before post-TAVI TTE was 84.8 (138.9) days; median 26  days.Standard trans-thoracic echocardiograms (TTE) were performed by trained British Society of echocardiography accredited cardiac physiologists using GE Healthcare machines. All standard echocardiography views were recorded. Captured images were subsequently downloaded onto discs and further analysed at a later date.Echocardiograms were analysed off-line using EchoPAC™ software (GE Vingmed Ultrasound AS Horten Norway. Version 0.201). Analysis was performed by a single blinded operator who was an experienced cardiac research physiologist. Echocardiogram measures were calculated according to British Society of Echocardiography specifications. Ejection fraction was calculated using Simpson`s biplane. The transmitral flow and isovolumic relaxation time (IVRT) were recorded by Doppler ultrasound. The E/A ratio was computed as a ratio of peak velocity in the early rapid filling phase when the ventricle relaxes (E wave) and peak velocity of the late filling due to atrial contraction (A wave) across the mitral valve during diastole. The myocardial performance index (Tei) was derived from the mitral valve closure to opening time and the left ventricle (LV) ejection time. LV mass was determined from septal and posterior wall thicknesses and LV end diastolic diameter and indexed to body surface area. Myocardial strain—the change in myocardial fibre length over the cardiac cycle—is a measure of myocardial muscle function that can be obtained using conventional assessment techniques and is an earlier marker of myocardial disease than ejection fraction. It was measured by tissue tracking analysis in the apical four chamber view and the parasternal short axis view centred on the left ventricle. All analysed segments were approved by both the programme and the operator. To assess for inter-observer variability, a second BSE accredited physiologist analysed 10 studies and results were compared. Krippendorff’s alpha intercoder reliability coefficient was 0.97 for the inter-rater reliability demonstrating very strong reliability between raters.Individual changes in GLS, PALS and GRS and subclinical improvements in LV function pre- and post-procedure were compared. PALS was derived from longitudinal strain curves generated for each of six atrial segments, obtained from the apical four chamber and two chamber views. GRS was averaged from regional segments as circumferential strain using the PSAX views at MV and PM level. Measurements of heart rate, left ventricular ejection fraction, left ventricular mass index, left ventricular dimension, left atrium dimension and E/e′ were incorporated. All analyses were performed on the GE Echo Pac v204 software.Ethical approval was granted by the local ethics committee, St James Hospital/Tallaght University Hospital Joint Research Ethics Committee (011006/16801). All participants in the study provided written informed consent to participate in the study.Descriptive analysis includes means  for continuous data and frequencies/percentages for categorical data. Paired t-test is used to compare changes pre- and post-valve implantation. All statistical analyses were carried out with Stata v17.0. Significance at p < 0.05 is assumed.A total of 25 participants were included in this study, 76% were male n = 19) and 24% (n = 6) were female. The mean age was 80.64 (SD 8.63). Patient characteristics are shown in Table 9 and 24%Our results revealed a significant improvement in GLS (mean change (post–pre) of 2.14%  (p = 0.0003) with no significant change in ejection fraction . Although there was a positive trend toward improvement in PALS, there was no significant difference post-TAVI and this reflected basic ejection fraction (EF) measurements which remained the same, mean change (post–pre) was 2.30% , p = 0.068. The mean change in radial strain was − 9.68% , p = 0.0058. Descriptive statistics pre- and post-TAVI are shown in Table Our findings show that TAVI led to significant improvements in both GLS and radial strain. In participants undergoing TAVI, measuring radial strain provided important prognostic information regarding improvements in LV function. Measuring PALS did not provide any statistically significant difference post-procedure. These findings are significant, as improvements in GLS have been shown to be inversely correlated with mortality in patients with reduced LV function and are a predictor of deterioration in cardiac function, future heart failure events and all-cause mortality –9. FurthOur findings are comparable to those of other similar studies. GLS appears to have a significant role but the significance of PALS and radial strain has been more ambiguous. These findings have been replicated in the short, medium and longer term post-TAVI. In the short term, a German study of 30 patients with severe AS undergoing TAVI showed significant improvements in GLS, with no changes in radial or circumferential strain and no difference in LVEF in participants comparing baseline echo to their echo one week post procedure . SimilarOther investigations have shown a more protracted time to accrue this benefit, in 150 patients undergoing TAVI in Germany, baseline GLS was similar to one week post TAVI but showed significant improvements at 3 months without any changes in circumferential strain or GRS. Interestingly, GLS was also directly correlated with post-procedural outcomes . An analFocusing on longer-term outcomes, these changes in strain have been shown to be associated with improved individual outcomes. Within 6 months of TAVI there was reverse LA remodelling and an improvement in LA reservoir function . In an IThe long-term sustained improvement in GLS post-TAVI has been shown in two studies of patients followed up a mean of 8 months post implantation with improvements in all three of strain, strain rate and twist, as well as in a population followed up for one year post-TAVI , 22. SimOur results show that use of deformation imaging to measure myocardial strain can lead to detection of subclinical changes in LV function which may be a predictor of patient prognosis post-TAVI. These findings are important, as from previous studies changes in GLS have been shown to be directly associated with clinical outcomes. Therefore, incorporating deformation imaging as adjunctive to standard echocardiographic measurements may provide additional information to risk-stratify patients based on LV function.In participants undergoing TAVI, measuring GLS provided important information regarding improvements in LV function which may have prognostic implications. GLS appears to have a significant role in predicting prognosis in patients undergoing TAVI. Measuring GLS may potentially have an important role in the management of this cohort of patients in the future, when coupled with the routine echocardiographic examination. In participants undergoing TAVI, measuring PALS may only be reflective of conventional measurements of systolic left ventricular function such as EF and may not reflect subclinical findings. Radial strain appears to have a significant role in predicting prognosis in patients undergoing TAVI. Measuring radial strain may potentially have an important role in the future management of this cohort of patients, in addition to the routine echocardiographic examination.This study was limited by a short follow-up period of 6 weeks. A longer follow-up period examining these echocardiographic parameters would be preferable to determine longer term changes in strain and LVEF. This study was also limited by varying follow up times between patients. An additional limitation was that blood pressure was not recorded at the time of participant TTE. Recommendations for future research would be to enrol a larger number of participants over a greater follow-up period, with incorporation of participant blood pressure at the time of TTE.


Fugl-Meyer Assessment scale for the upper limb and (b) elbow flexor spasticity, as reflected by the Tonic Stretch Reflex Threshold, in 41 patients with first-ever stroke. Hemiparesis and spasticity were affected by damage to peri-Sylvian cortical and subcortical regions and the putamen. Hemiparesis (but not spasticity) was affected by damage to the corticospinal tract at corona-radiata and capsular levels, and by damage to white-matter association tracts and additional regions in the temporal cortex and pallidum. VLSM conjunction analysis showed only a minor overlap of brain voxels where the existence of damage affected both hemiparesis and spasticity, suggesting that control of voluntary movement and regulation of muscle tone at rest involve largely separate parts of the motor network.Hemiparesis and spasticity are common co-occurring manifestations of hemispheric stroke. The relationship between impaired precision and force in voluntary movement (hemiparesis) and the increment in muscle tone that stems from dysregulated activity of the stretch reflex (spasticity) is far from clear. Here we aimed to elucidate whether variation in lesion topography affects hemiparesis and spasticity in a similar or dis-similar manner. Voxel-based lesion-symptom mapping (VLSM) was used to assess the impact of lesion topography on (a) upper limb paresis, as reflected by the  More than 80% of hospitalized subjects with stroke present some degree of hemiparesis, with upper limb (UL) involvement seen in about 75%2. Spasticity accompanies paresis at different rates (4-43%) in different time periods post stroke4. Hemiparesis and spasticity may lead to dependence in activities of daily living and reduced quality of life6.Stroke is a leading cause of adult long-term motor disability7.By ‘hemiparesis’ we refer in this article to pathological active movement comprised of reduced muscle strength and impaired movement control (precision and speed of voluntary movement) in the side of the body contralateral to the side of the stroke. The term ‘spasticity’ is used here as defined by James Lance, to denote velocity-dependent increment in muscle resistance to passive stretching, emerging from hyperexcitability of the stretch reflex arc9. A word on other forms of muscle hypertonia, different from spasticity, is in place. The term ‘spastic dystonia’ was coined by Derek Denny-Brown10 to denote a consequence of experimental brain damage in monkeys, where muscles are activated in a sustained manner affecting the animal’s posture in a typical way. Denny-Brown reported that this phenomenon is not abolished by dorsal rhizotomy . Thus, contrary to ‘spasticity’ as defined by Lance, ‘spastic dystonia’ cannot be attributed to the effect of increased afferent stimulation of spinal motor neurons by hyperactive muscle-spindles. It should rather be conceived as a sequence of damage to motor control mechanisms within the central nervous system (an efferent phenomenon), impairing the regulation of spinal motor neurons’ excitability10. In a recent review by Lorentzen et al.11, the term ‘spastic dystonia’ was used in a much similar way, to denote ‘stretch- and effort-unrelated sustained involuntary muscle activity following central motor lesions’, which contributes to the typical hemiparetic posture. In the resting hypertonic muscle, sustained involuntary neural activation (‘spastic dystonia’) is distinguished from hypertonia due to altered mechanical properties of muscles , by demonstration of sustained EMG activity despite intended relaxation, in the former but not in the latter state12. The important contribution of reduced mobility and disuse to the formation of intrinsic hypertonia was stressed by Dietz et al.13 and Gracies14, who proposed that the secondary soft tissue changes may affect in turn the expression of spasticity, spastic dystonia and other forms of muscle overactivity, by interaction with plastic changes occurring within the central nervous system . In recent years, important information has been gathered on the relative prevalence of spasticity vs. spastic dystonia among brain-damaged patients. Marinelli and colleagues17 established, using surface EMG recording, the existence of spastic dystonia in the rectus femoris muscle of 8 out of 30 patients with multiple sclerosis and velocity-dependent hypertonia. The other 22 patients exhibited only spasticity, as evidenced by their ability to relax their knee extensor muscles (and abolish the EMG activity) upon request17. Trompetto and colleagues18 found a higher prevalence of spastic dystonia in the flexor carpi radialis muscle of stroke patients exhibiting velocity dependent hypertonia . Recently, Puce and colleagues19 studied the electromyographic manifestations of hypertonic muscles in multiple sclerosis. EMG was recorded from muscles at rest, during stretch (dynamic stretch reflex) and during one minute immediately following muscle stretch (static stretch reflex). The expression of EMG activity in the three conditions differed in extensor and flexor muscles of the upper and lower limbs, providing novel insight into the heterogeneity of muscle hypertonia states in the upper motor neuron syndrome19.We have specified in this way the usage of the terms ‘hemiparesis’ and ‘spasticity’ in order to avoid confusion, as both terms are used in the clinical neurology and neuroscience literature in various ways, especially in discussions of components of the ‘pyramidal’ or ‘upper motor neuron’ syndrome and their underlying pathophysiology in humans and animalsThreshold Control (or Referent Control) Theory suggests that the nervous system controls posture and movement by specifying, in a task sensitive manner, a spatial point in the biomechanical range of a joint (muscle length/joint angle) where the stretch-reflex is activated and motoneuronal recruitment begins24. By stretching a completely relaxed muscle at different velocities, and observing the dynamic spatial threshold for the emergence of reactive contraction at each velocity, one can extrapolate the Tonic Stretch Reflex Threshold (TSRT), denoting the angular threshold for muscle spindle reflexive activation and the emergence of reactive muscle contraction in the resting state. To maintain a muscle relaxed throughout the entire biomechanical range, the TSRT has to be shifted outside of the biomechanical range25. Following brain damage, the ability to regulate the spatial thresholds for muscle contraction in a task-specific manner is impaired. In patients with spastic hemiparesis this impairment may lead to the inability to shift the TSRT outside of the biomechanical range in order to voluntarily relax muscles26. Consequently, attempts to passively or actively move the limb beyond the pathologically set TSRT evoke increased resistance, or spasticity. The Threshold Control Theory predicts that impaired regulation of motoneuronal excitation thresholds will lead both to spasticity and arm paresis30. The neural substrate involved in task-dependent threshold setting is largely unknown21.The precise relationship between spasticity and hemiparesis following stroke is far from clear. In motor-control theorizing, the 31. The MAS subjectively grades the amount of resistance felt during passive stretching of muscles on a 6-point ordinal scale33 and the FMA-UL tests the patient’s ability to execute different movements in a precise manner34. The MAS was found also to relate to muscle strength, such that patients with less strength in proximal and distal muscles of the hemiparetic UL  had a higher risk of developing spasticity as reflected by the MAS35, and poor strength in the hemiparetic UL (measured with Upper Extremity Motricity Index) on admission to rehabilitation was the most effective predictor of moderate to severe spasticity measured by the MAS36. Recently, our group showed links between the severity of spasticity post stroke (as reflected by the TSRT and the MAS) and stochastic measures of the distance between pathological and normal elbow movement. Thus, subacute stroke patients with spasticity exhibited reaching motion that was less similar to the motion of healthy subjects. This was reflected by high bi-directional Kullback-Liebler divergence and Hellinger’s distance measures38.From a clinical perspective on the relationship between hemiparesis and spasticity, patients with elbow/wrist spasticity, measured with the Modified Ashworth Scale (MAS), were found to have significantly lower scores on the Fugl-Meyer Assessment scale of the hemiparetic UL (FMA-UL) compared to patients without elbow/wrist spasticity39. The idea that spasticity contributes to the development of hemiparesis is based largely on the hypothetical assumption that the attempted voluntary activation of the agonist muscle in a joint causes the hyper-excitable reflex arc in the antagonist muscle to react by co-contraction, thus slowing down or even preventing the intended movement (‘co-contraction paresis’). However, slow and abnormal elbow movements made by patients with chronic stroke were shown to be more related to the degree of maximal isometric torque that the agonist muscle could generate than to the level of muscle spasticity in the antagonist. Actually, antagonist activity during movement was at or below the normal range even in patients with marked hypertonus at rest in the antagonist muscle40. Spasticity was found to explain only part of the deviation from normality observed in movement kinematics. Thus, peak reaching velocity in the hemiparetic UL was shown to be affected mainly by the reduction in muscle strength, rather than by the level of spasticity . End-point error and reach path curvature were influenced mainly by individuation index, with spasticity explaining a smaller portion of the variance41.On the other hand, there is empirical evidence which points to non-correlated and even discordant relations between paresis and spasticity post stroke. One often sees patients with complete hemiplegia who are hypotonic in the paretic side. Spasticity develops only in about a third of hemiparetic patients and severe paresis is seen almost as often in patients with and without spasticity48. Some studies addressed also lesion effects on spasticity52. Hemiparesis was associated in most cases with damage to white-matter regions containing the corticospinal tract  and association fibers , sensory-motor cortex, insular and peri-Sylvian opercular cortical regions and the putamen48. Spasticity was found to relate to damage to the insula, premotor cortex, thalamus, basal ganglia, and white matter regions including the internal capsule, corona radiata and external capsule52. However, these studies did not disclose the extent of network sharing between hemiparesis and spasticity at the voxel level. As each of the above structures is comprised of hundreds and thousands of brain voxels, hemiparesis and spasticity could be affected by same or different voxels within a given structure.The impact of variation in stroke lesion topography on the expression of hemiparesis was studied extensively33 as a marker of muscle hypertonia. The MAS, which is widely used as a clinical measure of spasticity, is based on subjective assessment by the examiner of the amount of resistance felt when the limb is passively stretched. Passive stretching is done usually at a non-specified velocity, despite the strong velocity dependence of hyper excitable stretch reflex activity assumed to underly spasticity53. The validity of the MAS has been questioned57 and the reported values for MAS inter-rater and intra-rater reliability are variable (inter-class correlation coefficients [ICCs range = 0.54–0.85]60.Past studies of lesion effects on spasticity used the MAS61), we identified brain voxels where the existence of damage affected the severity of hemiparesis (as reflected in the FMA-UL score) and brain voxels where the existence of damage affected the severity of spasticity (as reflected in TSRT measurement). This is the first time TSRT rather than the MAS is used in a lesion study of spasticity. VLSM conjunction analysis was applied to assess the extent of network sharing at the voxel level. As the study was conducted in the subacute period following stroke, we hypothesized that both paresis and spasticity would be affected by damage to brain structures involved in the control of movement in the intact brain, as well as structures supporting motor recovery processes. Given the evidence for often discordant relations between the magnitude of hemiparesis and spasticity41, we hypothesized that VLSM conjunction analysis may reveal both common and distinct brain voxels affecting these two components of the upper motor neuron syndrome. In the current study we aimed to determine the impact of variation in lesion topography on paresis and spasticity of the contralesional UL. Using voxel-based lesion symptom mapping (VLSM62. Patients were included if they (1) had a single, first-event stroke in middle cerebral artery territory, confirmed by magnetic resonance imaging or computed tomography; (2) were in a stable clinical and metabolic state; (3) were 25–80 years of age; (4) were in the sub-acute phase of the disease (3 weeks to 6 months post stroke onset); (5) had arm paresis (2–6/7 on the Chedoke-McMaster Stroke Assessment arm score63), but were able to perform at least 30° voluntary elbow flexion and extension; (6) had elbow flexor spasticity; (7) were able to provide informed consent. In order to minimize variance in premorbid structure–function relationship we aimed to recruit only right-handed persons, but eventually only 37 of the 41 participants comprising the study cohort were right handers and four were actually ambidextrous. Exclusion criteria were the presence of other neurological or major neuromuscular/orthopedic problems, pain, or difficulty comprehending instructions. All experimental protocols were approved by the Institutional Review Board/Ethics Committee of Loewenstein Rehabilitation Medical Center, Raanana, Israel; Institutional Ethic Committee of the Tel Aviv University, Tel-Aviv, Israel; Center for Interdisciplinary Research in Rehabilitation, Montreal, Canada; Institutional Ethics Committee of Kasturba Hospital, Manipal, India; and Manipal University, Manipal, India. All experiments were performed in accordance with relevant guidelines and regulations. Participants signed informed consent forms approved by institutional review boards of Loewenstein Rehabilitation Medical Center, Raanana, Israel; Institutional Ethic Committee of the Tel Aviv University, Tel-Aviv, Israel; Center for Interdisciplinary Research in Rehabilitation, Montreal, Canada; Institutional Ethics Committee of Kasturba Hospital, Manipal, India; and Manipal University, Manipal, India. The current cohort included stroke patients who participated also in our recently published study64, but only those who met the aforementioned inclusion criteria. Individual patients’ data are shown in supplementary Table Forty-one first-event stroke patients who sustained a stroke 2.2 ± 1.3 months previously participated. Data were collected in the framework of the ENHANCE study66 was used for evaluation of hemiparesis. The FMA-UL contains 33 test items for the hemiparetic UL. These items are divided into four subsections: shoulder-arm, wrist, hand, and upper-limb coordination. Each test item is scored on a 3-point ordinal scale , with a maximal total score of 66 points.The standardized sensitive, reliable and valid FMA-UL64) determined the TSRT in the Biceps Brachii (BB) muscle from a series of dynamic stretch reflex responses evoked by a clinician stretching the elbow flexors at different velocities. After preparing the skin, active bipolar electrodes  were placed above the bulk of the BB  and the Triceps Brachii  based on known anatomical landmarks and palpation. A high-resolver electrogoniometer  was attached with straps to the lateral aspect of the arm and forearm with the axis of rotation aligned with the lateral epicondyle. Participants sat with the arm resting in slight abduction on a pillow. At the start of testing, participants performed an isometric maximal voluntary contraction of elbow flexors to adjust the electromyography (EMG) gain. The elbow starting angle was set to the maximal flexion allowed by the approximation of the arm and the forearm but without contact between the two segments (± 10°). The forearm was in the neutral position between pronation and supination. The baseline EMG signal and the initial elbow angle were reproduced prior to each stretch. A trial consisted of stretching the forearm from the initial position towards full extension (180°) and returning the forearm to the starting position. Before each stretch, a randomly assigned speed, equally distributed between slow, moderate and fast velocities, was indicated to the evaluator by an auditory signal from the MSM. Stretch velocities were randomized to avoid anticipation of the upcoming stretch velocity. Twenty stretches were performed with a resting period of at least 10 s between stretches to minimize effects of stretch-reflex habituation68. Participants were instructed to relax completely. For each stretch, the MSM identifies the angle and velocity at which the evoked stretch response is elicited . The TSRT angle (at rest) is calculated by extrapolation of a linear regression line through these dynamic angle/velocity thresholds to zero velocity. More severe spasticity is expressed by a smaller TSRT angle. A detailed description of TSRT recording and analysis is provided in Frenkel-Toledo et al.64.The Montreal Spasticity Measure . The MAS is measured on a six-point ordinal scale  to subjectively rate the resistance to passive stretching. In the current study we aimed to maintain a stretching velocity of approximately 100°/s69, Automated Anatomical Labeling (AAL) atlas71, Volume Occupancy Talairach Labels (VOTL) atlas71 or the White Matter Atlas72. Quantification of the amount of tissue damage within each structure/region of the atlas was obtained as described earlier73. In the current study, tissue damage in the normalized brain was reported using the interface to the AAL and white matter atlases. Registration accuracy of the scans to the MNI template71 across all subjects ranged from 89.2% to 94.2%.Delineation of lesion boundaries was done manually on digitized follow-up brain CT or MRI scans, dated on average 30 days post stroke onset, by a physician highly experienced in analysis of neuro-imaging data, who was blinded to all other participants' information (author NS). Lesion analyses were performed with the Analysis of Brain Lesions (ABLe) module implemented in MEDx software . ABLe characterizes brain lesions in MRI and CT scans of the adult human brain by spatially normalizing the lesioned brain into Talairach space using the Montreal Neurological Institute (MNI) template. It reports tissue damage in the normalized brain using an interface to the Talairach Daemon 61 was used to identify voxels (2 × 2 × 2 mm) of the normalized brain where the existence of damage has a significant impact on the FMA-UL as a measure of UL paresis, and the BB TSRT as a measure of elbow flexor spasticity. Voxel-by-voxel analysis was used to calculate the statistical significance of performance difference between subjects with and without damage in a given voxel, using the Mann–Whitney test . Only voxels damaged in at least 20% of the subjects were tested, and at least 10 adjacent voxels had to show a statistically significant impact of damage on performance for a cluster of voxels to be reported76. To correct for multiple comparisons, voxels with values exceeding a false discovery rate (FDR) of p < 0.05 were considered significant77. However, due to insufficient statistical power in the VLSM analysis of TSRT, the results in this analysis did not survive the FDR correction for multiple comparisons and we report for this analysis anatomical regions containing clusters of at least 10 voxels, where patients affected in these voxels showed disadvantage relative to patients who were not affected in these voxels, using a lenient criterion of p < 0.018 . The maximum z-score is reported for each cluster of contiguous above-threshold voxels. Since there may be multiple voxels with this maximum z-score in the cluster, we report the coordinates of the voxel that is most superior, posterior and left in its location within the cluster . The AAL atlas for gray matter and the White Matter Atlas72 were used to identify the brain structures in which the significant clusters were located. VLSM conjunction analysis was used to classify ‘significant’ voxels  as affecting (1) both the FMA-UL and TSRT; (2) only the FMA-UL scores; and (3) only the TSRT scores. Because of the relatively small sample size of the cohort, VLSM and conjunction analyses were conducted on the entire cohort, after flipping the scans onto a single (left) hemisphere template. The results after flipping onto the right hemisphere are very similar except for some differences in the number of voxels in some regions due to subtle differences in the extent of homologous regions in the two hemispheres.VLSMDemographic and clinical information as well as FMA-UL and TSRT scores are described in Table Overlay lesion map (stroke lesion distribution) of the entire cohort is shown in Fig. 53 identified clusters of voxels where the existence of damage was associated with significantly more severe UL paresis (lower FMA-UL scores) and greater BB spasticity  in the contralesional UL  vs. spasticity (TSRT of the BB). To our knowledge, this is the first attempt to investigate the effects of lesion topography on hemiparesis vs. spasticity at the voxel level. This is also the first analysis of the impact of variation in lesion topography on the TSRT.The number of brain voxels in which the existence of damage had an impact on the severity of UL paresis (FMA-UL score) was much larger than the number of brain voxels in which the existence of damage had an impact on spasticity (BB TSRT). Moreover, the number of cortical regions and subcortical structures hosting the ‘significant’ voxels, was much larger in the case of hemiparesis compared to spasticity Table .48 and our own study in a different cohort43. The findings point to the central role of the ipsilesional CST in mediation of cerebral control over the spinal motor activity that drives movement in the hemiparetic UL81. The evidence for that from lesion studies is corroborated by motor evoked potentials research83. The significant impact of damage to centrally located cortical regions outside the primary motor cortex (M1) and the salient impact of damage to white matter association tracts and the basal ganglia, point to the wide network that supports the planning and execution of voluntary movement86 and to the involvement of various network components in the re-organization of cerebral motor control occurring in the subacute period (first months) following a stroke88. Plastic changes taking place at this time should relate to various components of motor activity, such as integration of somato-sensory and visuospatial information into motor plans, and acquisition of new motor skills through procedural learning. This suggests that brain regions beyond the premotor and motor cortices take part in the process89. Notable among the cortical components of the re-organizing network is the insula, in which the existence of damage to almost half of its voxels was found to affect patients’ FMA-UL scores. This finding points to an important role of the insular cortex in motor behavior91. The insula is known to be involved in the execution of arm movements in the gravitational field92. The insular cortex and temporal pole were shown to encode movement direction in a center-out motor task93, and the middle temporal gyrus was shown to be involved in encoding path-related information during a center-out motor task94. The involvement of nonmotor regions such as insula, temporal pole and the middle and superior temporal gyri point to their role in adaptive remapping processes supporting recovery95. Our finding pointing to the importance of the superior longitudinal fasciculus, is in line with past demonstration that microstructure of this major white-matter association tract predicts stimulation-induced interference with on-line motor control96. Also note that damage to M1 voxels was not shown in the current VLSM analysis to have a significant impact on hemiparetic UL movement. This somewhat unexpected finding is explained by the relatively infrequent involvement of the more dorsal parts of the precentral gyrus, hosting the M1 hand and arm areas, in the stroke process, as can be seen in the lesion overlay map of the current cohort , UL paresis was related to damage in brain voxels residing in centrally located cortical regions , the CST , different white-matter association tracts , and the putamen and pallidum parts of the basal ganglia. These results are in line with earlier lesion studies of hemiparesis52. The putamen was identified as the site most tightly associated with spasticity in a VLSM study by Cheung and colleagues50. Yet, in contrast to the findings of the current research, in these earlier studies, spasticity was related also to damage in the premotor cortex, thalamus and white-matter projection  and association  tracts—a distribution of areas quite similar to our findings with respect to UL paresis. These studies used the MAS as a measure of spasticity, whereas we used TSRT. Moreover, in the earlier studies, spasticity was assessed in different proximal and distal UL muscles, whereas in the current study, only spasticity generated in the BB was used. These differences may explain the more restricted network emerging in the current study, relative to the previous studies52. As mentioned before, TSRT and MAS assess different aspects of spasticity. TSRT is a measure derived from a specific line of motor control theorizing (Threshold or Referent Control Theory26), where the severity of impairment in regulation of stretch reflex activity is represented by the spatial threshold (angle) in the joint range of motion at which the hyperactive stretch reflex begins to act. The MAS, in contrast, measures the amount of supra-threshold resistance produced by the stretched muscle53, without considering the joint angle at which pathological resistance begins. In past research, TSRT values did not correlate with MAS scores in spastic elbow flexor muscles, in patients assessed at the sub-acute64 and chronic97 stages post stroke onset. In the current study, VLSM of MAS results did not yield voxel clusters where the existence of damage exerted a statistically significant effect on the test scores . This divergence from past lesion studies using the MAS is probably related to the fact that patients had to be capable of producing 30° flexion–extension elbow movements with the hemiparetic UL in order to be recruited to the current study. Consequently, the cohort here did not include patients with severe spasticity in elbow flexors  and in the external capsule and putamen. Thus, the anatomical network related to spasticity was more restricted than the network related to hemiparesis, despite the use of a more lenient criterion of significance in the case of spasticity, as the results of the VLSM analysis for spasticity did not survive the FDR correction for multiple comparisons. In previous research, spasticity was also found to relate to damage in the insular cortex, basal ganglia and external capsule18, we should assume that in part of the patients, velocity-dependent increment in muscle resistance to passive stretching, emerging from hyperexcitability of the stretch reflex arc , was accompanied by co-occurring involuntary tonic activation of resting muscles (spastic dystonia16). The anatomical network identified here by VLSM of TSRT results may have been influenced by the co-occurrence of spastic dystonia. In stroke patients in whom neurally-mediated muscle hypertonia of the UL results from spasticity only—a minority of the stroke population according to Trompetto et al.18—the anatomical network is likely to be more restricted.As the assessment of muscle hypertonia in the current study is based on MAS and TSRT measurements only, i.e., measurements informative on properties of the dynamic component of the tonic stretch reflex (how the muscle behaves during the time period of the stretch), it is impossible to exclude the possibility that in part of the cohort muscle hypertonia was contributed by spastic dystonia. Note that the measurement of the TSRT was based on determination of the point where the EMG signal of the stretched muscle increased and remained 3SDs above the background EMG level for 25 ms. The patient was required to relax the elbow as much as possible prior to the stretch, in order to permit a reliable assessment of the spatial location where this EMG dynamics occurred during the stretch. Despite the fact that MAS scores in the cohort did not surpass the lower range (1–2), in part of the patients the background EMG was not abolished completely during the attempted relaxation prior to the stretch. Thus, although we did not employ a standardized recording of surface EMG at rest, as done in order to establish the presence of spastic dystoniaThe results of the VLSM conjunction analysis, stratifying brain voxels where damage affects hemiparesis only, spasticity only, or both hemiparesis and spasticity Fig. , Table 399. On the other hand, the absence there of voxels in which the existence of damage affects the severity of spasticity , raises questions on the role of CST damage in spasticity.The presence, within the trajectory of the CST, of brain voxels in which the existence of damage affects the severity of hemiparesis, is expected, given the crucial role played by the CST in mediation of cerebral control over voluntary movement9. One key question is whether CST damage, which is widely recognized as the main determinant of the severity of hemiparesis81, also plays a direct role in the formation of spasticity. Demonstrations of paresis, or at least the loss of precision (dexterity) in voluntary movement—without spasticity—following experimental lesioning confined to the CS tracts in macaque monkeys102 and other animals103 were taken as empirical evidence that CST damage is not the prime cause of spasticity106. There are case reports pointing to the emergence of hemiparesis without spasticity following damage confined to the CST in humans108. However, most of the empirical evidence in favor of a non-pyramidal mediation of spasticity comes from animal research, and claims have been made against direct extrapolation from even high non-human primates to humans, given the significant variation in functional neuroanatomy of descending projection tracts between the species98. As said, a different aspect of the severity of spasticity, not expressed in the TSRT value, i.e., the magnitude of resistance to passive stretching, as assessed by the MAS, was shown in past lesion studies to have a more extensive anatomical correlate compared to our TSRT anatomical correlates, including an effect for pyramidal tract damage52.The underlying mechanism of spasticity and its relation to other components of the ‘upper motor neuron’ or ‘pyramidal’ syndrome is a matter of long-lasting debateThreshold Control (or Referent Control) Theory26 which forms the theoretical foundation for using the TSRT as a measure of spasticity, offers testable predictions concerning a wide range of normal and pathological motor behaviors21. However, the neural mediators of task-sensitive referent control are far from clear. In the current study, the functional anatomy of referent setting was tested, for the first time in the brain-voxel resolution level, with respect to muscle tone regulation at rest. Pathological setting of the spatial threshold for muscle-spindle recruitment by passive stretching was found to relate to a number of brain structures—the Rolandic operculum, superior temporal and insular cortical regions and the external capsule and putamen. These structures contained voxel clusters where the existence of damage affected the severity of spasticity as reflected by the TSRT. Damage to a minority of these voxels also affected the severity of hemiparesis, possibly pointing to some commonality in the cerebral mechanism mediating the implementation of referent control in voluntary movement as well as in muscle tone regulation. Overall, our findings support the view that the cerebral neural network controlling voluntary movement is much larger than the cerebral network controlling muscle tone at rest. Our findings seem to show that in conditions of hemispheric stroke, damage to the pyramidal tract in itself is insufficient to evoke the aspect of spasticity reflected in the TSRT value. In terms of the Referent Control Theory, this would be the magnitude of deviation from normality when setting the spatial threshold for muscle-spindle signaling in the resting muscle.The 7, is widely thought to emerge from failed balancing of excitatory and inhibitory descending signals of supraspinal origins, though much is still uncertain in this respect109. One suggestion emphasizes the role of the ‘extrapyramidal’ reticulospinal and vestibulospinal descending tracts . Thus, the dorsal  RST is thought to provide an inhibitory effect on the stretch reflex, while the medial (pontine) RST and the VST provide excitatory inputs to the stretch reflex. The dorsal RST receives facilitatory stimulation from the contralateral motor cortex via corticoreticular projections, which run in close proximity to the CST and are often affected together by the stroke process. Reduced inhibition from the dorsal (medullary) RST and/or increased excitation from the unopposed medial (pontine) RST and VST  lead to hyperexcitability of the muscle spindle reflex arc and to muscle hypertonia106. However, in decerebrated cats in whom the VST was destroyed (in the floor of the fourth ventricle), the limbs in the side as the VST lesion were flaccid, the stretch reflex in the knee extensor muscles was diminished or absent, and the ipsilateral knee jerk was pendular, prolonged and more readily inhibited than that on the opposite side110. The current lesion study cannot inform much on the specific contributions of brainstem descending pathways to regulation of muscle tone at rest. As all the patients recruited for this study had hemispheric strokes in MCA territory, all posterior fossa structures, including the cell assemblies in the tegmentum of the brainstem from which descend the above tracts, were not involved in the stroke process.Spasticity, viewed as a manifestation of hyper-excitability of the stretch reflex arc111. The FMA-UL and TSRT were assessed here in the sub-acute period (2.2 ± 1.3 months after onset), when the patients were hospitalized for rehabilitation. In the subacute period, behavioral improvement is most salient, reflecting resolution of secondary damage and edema, and improved physiological state in peri-lesional cortex where adaptive remapping processes take place116. Therefore, task performance at the early sub-acute phase is influenced, on one hand, by the relation of lesion topography to the pre-morbid localization of the neural network that supports the tested behavior, and on the other hand, by the emerging effects of natural and treatment-related neuroplasticity. Lesion effects on behavior tested later, in the chronic phase, differ from the effects observed in the acute and subacute periods, because the impact of damage to the relevant pre-morbid neural network subsides with the maturation of functional re-mapping and reorganization processes which take place in peri-lesional and other brain regions116. Thus, the behavioral impact of damage to a given brain structure is more likely to reflect the natural structure–function relationship when task performance is measured shortly rather than lately after the onset of stroke111.Interpretation of lesion analyses concerning the neural substrate of a given behavior should take into consideration the time interval between the occurrence of structural damage (stroke onset) and behavior assessment63 does not specify the trajectory of cortico-reticulo-propriospinal fiber tracts and other descending tracts controlling extra pyramidal activity; therefore, we could not assess the possible contribution of damage to these tracts to spasticity and hemiparesis. Second, the VLSM results for the TSRT are based on a lenient criterion, as the results did not survive the FDR correction for multiple comparisons. These results are likely to reflect a trend that may become significant with larger numbers of subjects, although they may also represent a type-1  error. Third, we failed to show in the VLSM analysis of MAS results voxel clusters where the existence of damage exerted a statistically significant effect on the test scores. This negative finding probably relates to the fact that patients had to be capable of producing 30° flexion–extension elbow movements with the hemiparetic UL in order to be recruited to the current study. Consequently, the cohort here did not include patients with severe spasticity in elbow flexors . Fourth, the measure of UL paresis used here (FMA-UL) reflects impaired movement in the entire limb, whereas the measure of spasticity (TSRT of BB) is driven from a single muscle. We do not know the extent of anatomical sharing between brain regions involved in regulation of muscle tone in different muscle groups. Moreover, it is common in spastic hemiparesis for different muscles acting on a joint  to exhibit different levels of spasticity. Thus, the relative paucity of brain voxels connected with spasticity in the current study could be affected by the fact that spasticity was quantified here only in one muscle. Fifth, we did not employ a standardized recording of surface EMG at rest, to see if the patients who participated in the study were able or not to abolish all neural activation of muscles at willed relaxation. Thus, uncertainty remains as to the possible contribution of spastic dystonia to the findings.Several limitations in the study should be acknowledged. First, the current analysis precluded the assessment of lesion impact on additional, potentially relevant, brain regions, because: (a) only voxels damaged in at least 20% of the cohort entered the VLSM analysis . Given the number of subjects in the current cohort n = 41), it was not possible to assess the impact of damage to relevant brain voxels of the more dorsomedial parts of the sensory-motor cortex, including the hand and arm parts of M1/S1, where the prevalence of damage was lower than this threshold  and spasticity (TSRT of spastic elbow flexors). We show that following stroke, hemiparesis and spasticity of the UL are affected differently by lesion topography, with minor anatomical overlapping. The differences, along with the small voxel overlapping, are likely to underlie the complex relationships (comorbidity and divergence) between the manifestation of paresis and spasticity in the upper motor neuron syndrome.Supplementary Table S1.


The utilization of left ventricular assist devices (LVADs) in end-stage heart failure has doubled in the past ten years and is bound to continue to increase. Since the first of these devices was approved in 1994, the technology has changed tremendously, and so has the medical and surgical management of these patients. In this review, we discuss the history of LVADs, evaluating survival and complications over time. We also aim to discuss practical aspects of the medical and surgical management of LVAD patients and future directions for outcome improvement in this population. Between 2013 and 2016, the prevalence of heart failure in the United States of America (USA) was estimated to be 6.2 million and trending upward [When considering the advanced heart failure population—a subgroup of patients with markers of severe disease who carry a particularly elevated mortality risk—heart transplantation was regarded as the only therapy with a meaningful impact on survival until recent years. Nevertheless, transplantation presents a number of challenges and limitations. In particular, the limited number of organs available and wait list mortality galvanized research into mechanical support as an alternative strategy to improve outcomes in advanced heart failure. The initial goal was to create mechanical pumps able to assist the left ventricle in its function of pumping blood to the aorta, avoiding major thrombosis, thereby allowing patients to survive in the outpatient setting until a donor heart became available. In order to do this, the device needed to be implantable in the patient’s chest, portable, and electrically powered. In 1994, the first pneumatically driven left ventricular assist device (LVAD) was approved as a bridge to transplantation (BTT) by the Food and Drug Administration (FDA) . A few yThe large size and limited mechanical durability of the initial pulsatile LVADs led to the development of a new generation of devices leveraging continuous-flow, rotary-pump technology. These pumps were much smaller and could therefore be utilized in smaller-sized patients; in addition, they had a single internal rotor, greatly limiting the number of moving parts subject to “wear and tear”. In a prospective observational study, continuous-flow LVADs were implanted as a bridge to transplant in 133 patients  and provided effective hemodynamic support  [Despite the increase in durability and survival and the reduction in severe adverse effects, axial pumps continued to carry significant morbidity and mortality compared to heart transplantation.The third-generation devices succeeded in further reducing friction to minimize thrombosis within the continuous-flow pump and in further reducing size to allow for minimally invasive implantation techniques. The contemporary LVAD pumps, HeartMate 3 and HeartWare Ventricular Assist Device (HVAD), are intra-pericardial, directly implanted in the left ventricle . While tAdvances in the configuration and technology related to these new-generation devices were reflected in further improvements in outcomes. In a multicenter prospective study of 140 patients eligible for transplant, HVAD was found to be non-inferior to a contemporary cohort of BTT patients from the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) database  .The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial compared the outcomes of BTT and DT patients randomized to the new centrifugal pump (HeartMate 3) versus axial pumps (HeartMate II) . Among 3In the INTERMACS registry, the survival of patients with LVADs has improved over time. In a recently published report, the 1-year survival rate for patients implanted between 2015 and 2019 was 86.8% for BTT and 80.1% for DT . These pA gap still exists between LVAD and heart transplant survival outcomes. In fact, 1-year mortality post-transplant is about 10% . As mentOverall, treatment of end-stage HF with an LVAD consistently improves patient quality of life ,15. AfteIt is important to acknowledge that LVAD patients continue to present a high rate of hospitalization (more than 30% at 90 days and more than 70% at 12 months) [The main goal of the team caring for LVAD patients is to obtain longer survival while minimizing adverse events. In order to achieve this goal, the following need to be addressed and optimized: (1) patient selection, (2) surgical management, and (3) medical management for the prevention and treatment of adverse events.The International Society of Heart and Lung Transplantation (ISHLT) recently issued updated guidelines regarding the selection of appropriate candidates for durable mechanical support devices . EvaluatGiven the intrinsic high mortality associated with advanced heart failure, the timing of LVAD implantation and pre-operative optimization are crucial. Risk stratification tools such as the Seattle Heart Failure Model may help decision making in this setting ,26. In aIn order to select the appropriate candidates to undergo LVAD implantation, an extensive evaluation is carried out. Tests are conducted to confirm indications and rule out contraindications. Each system needs to be assessed and discussed in a multidisciplinary forum in order to devise an individualized plan for the patient. Key components of the pre-operative evaluation are summarized in Psychosocial considerations are critical to the selection and management of LVAD patients. Current guidelines for mechanical circulatory support recommend assessing psychosocial factors including social support, mental illness, cognitive function, substance abuse, adherence behaviors, health literacy, housing, and financial support ,27,28. PWhile recent evidence indicates that there is a limited impact of psychosocial factors on survival after LVAD implantation, their impact on readmission and adverse events has been consistently shown ,30,31,32Some psychosocial factors are essential for LVAD candidacy. Patients must have a dwelling with adequate access to power to operate the LVAD equipment safely, sufficient cognitive function to operate and manage the pump, health coverage to cover costs of life-saving medications such as anticoagulants that prevent pump thrombosis, and a caregiver who can support the LVAD patient during the transition from the hospital to home care with vital caregiving duties  ,27. The The influence of additional psychosocial factors like health literacy, mental illness, adherence behaviors, and substance abuse is more subjective. Each of these factors has been shown to increase the risk of readmission after implant or has been associated with an increased risk of having an adverse LVAD event ,35,36. AThe two most common approaches for LVAD implantation are median sternotomy and a bi-thoracotomy approach. Methods of LVAD implantation without the use of cardiopulmonary bypass have been described, but they are not widely adopted ,39. In gThe key objectives of LVAD implantation include (1) establishing an unobstructed inflow cannula position in the left ventricle and (2) properly positioning the outflow graft anastomosis without obstruction or kinking. The only currently available FDA-approved LVAD, the HeartMate3, like the historical HVAD and HeartMate II devices, was designed to pass an inflow cannula through the apex of the heart. This cannula is ideally directed toward the mitral valve in order to optimally drain blood from the LV through the outflow graft into systemic circulation. Misalignment of the inflow cannula can result in thrombotic events due to a greater propensity for areas of blood stagnation within the LV. The optimal site for inflow position is usually around the apex of the LV.The usual site for outflow graft anastomosis is the ascending aorta, although alternative sites such as the axillary artery or descending aorta have also been utilized. In general, the outflow graft should be sized such that it can travel across the midline along the inferior margin of the heart before gently bending cranially to travel along the right atrium to the right of the sternal midline to then finally reach the ascending aorta . ExcessiThe general principles that must be achieved are the same for DT or BTT LVAD implantation. However, given that a second operation is necessarily planned for BTT patients, there are some special considerations with BTT implantation, so as to reduce the risk of re-entry injury at the time of transplantation. The conventional approach to LVAD implantation has been through median sternotomy. However, the bi-thoracotomy approach has also been popularized in many centers. There are pros and cons associated with each technique ,41,42.The median sternotomy approach is the most familiar incision for cardiac surgeons. It allows for the best possible surgical exposure. Usually, there is minimal postoperative pain with this approach, as compared to other ports of access to the chest. It allows for ease of optimal placement of the inflow cannula and outflow graft.The less invasive approach includes a bi-thoracotomy incision in the left lateral chest wall over the left ventricular apex area to place the inflow cannula and in the right second intercostal space to place the outflow graft ,41,42. TIschemic and hemorrhagic strokes are a relatively common LVAD complication that occurs at a rate of 0.08 to 0.27 events per patient per year . In thisLVAD patients often present the classic cardiovascular risk factors associated with a higher risk of stroke. However, other LVAD-specific factors have been reported to further increase this risk. For instance, ischemic strokes in LVAD patients originate not only from atherosclerotic disease, but also from embolization of thrombi formed in the LVAD itself, outflow graft, intracardiac chambers, or aortic root ,46,47. TAt the same time, LVAD patients are prone to bleeding due to the need for anticoagulation and antiplatelet therapy, but also due to acquired deficiency of Von Willebrand factor, secondary to shear stress from continuous flow. Intracranial bleeding in LVAD patients can be spontaneous or due to hemorrhagic transformation of an ischemic stroke, or septic emboli, among other mechanisms.Additionally, there is a clear association between the risk of stroke and device type. The HM3 has been shown to be associated with lower ischemic stroke risk than the HMII ,49. BlooUnlike the left ventricle, the right ventricle (RV) is a highly compliant, thin-walled, crescent-shaped chamber that usually works in a low-pressure, low-resistance system. Around 10 to 40% of people who receive an LVAD develop right ventricular failure early during the post-implantation period, leading to poor outcomes ,52,53. SAlthough at this point there are no proven medical therapies available to prevent or treat right ventricular failure, there are several interventions that can provide adequate support while a more favorable hemodynamic status is re-established. These include inotropic or temporary mechanical circulatory support of the right ventricle, pulmonary vasodilators such as phosphodiesterase inhibitors, volume optimization, and hemodynamic and echocardiographic LVAD speed optimization targeting minimal mitral regurgitation, to avoid displacing the septum excessively into the left ventricle . PreservAfter infectious complications, gastrointestinal (GI) bleeding is the most common problem seen in LVAD patients, affecting up to 40% of this patient population . There aIn the setting of gastrointestinal bleeding, the treatment goal is to ensure hemodynamic stability by providing transfusions as needed and, in selected cases, by partially reversing the INR while considering the risk of LVAD thrombosis. Esophagogastroduodenoendoscopy (EGD), colonoscopy, and video capsule endoscopy can provide essential information to rule out other etiologies of gastrointestinal bleeding and to guide therapy. Endoscopy allows for direct intervention on the arteriovenous malformations that are most frequently the cause of GI bleeding.The usual target INR for LVAD patients is 2.5, with a range of 2–3 . A subthDriveline exit site infections are among the most common complications observed in LVAD patients . Risk faSome examples of patient characteristics that increase the risk of driveline infections are obesity, younger age, worse constitution, and longer time on device support . Co-morbStrategies to prevent driveline infections include ensuring that the velour part of the driveline is entirely within the tissue tunnel, using fixation anchors to maintain optimal driveline position, having a standardized dressing change protocol with strict sterile technique, and patient education .Once a driveline infection is diagnosed, treatment depends on the organism isolated and on characteristics of the host. In the majority of cases, chronic suppressive antibiotic therapy is needed due to an inherent inability to achieve source control. As many organisms are biofilm producing, curative antibiotic therapy is not feasible. The only definitive therapy is LVAD explantation (recovery or transplant).Despite tremendous advances in technology and improved outcomes over the last two decades, VAD therapy remains far from optimal for end-stage heart failure patients. Currently, it remains saddled by undesirable complication rates and significant quality-of-life barriers. The future of VAD therapy should aim to achieve the same long-term survival rates as cardiac transplantation, while minimizing the negative impact on quality of life. Incremental improvements currently being developed include enhanced blood-pump interface, fluid dynamics, and impeller engineering to improve hemocompatibility and reliability. More revolutionary goals include a ‘smart’ VAD that modulates pump flow to adapt to dynamic physiological needs and perhaps simulates more natural pulsatile flow synchronized with the patient’s native heart residual contractility. Early developments of such a dynamic VAD in simulations and animal models have been published, and the results are encouraging ,73,74,75In addition to improving the VAD hardware, the future of VAD therapy also depends on improving the software that controls and monitors VADs. New technology such as machine learning is poised to take on an important role in VAD therapy in the future. Machine learning may be used to monitor VAD operating metrics for early detection of VAD complications or to identify physiological changes such as volume status and arrhythmias. Initial proof-of-concept studies leveraging machine learning to detect VAD suction, impending pump failure, and arrhythmias have been published ,78,79. IWith these technological enhancements, a future generation of VADs whose outcomes exceed those of cardiac transplantation is finally within reach.


Women with advanced heart failure receive advanced surgical therapies such as durable left ventricular assist device (LVAD) implantation or heart transplantation at a rate much lower compared to males. Reasons for this discrepancy remain largely unknown. Much of what is understood reflects outcomes of those patients who ultimately receive device implant or heart transplantation. Females have been shown to have a higher mortality following LVAD implantation and experience higher rates of bleeding and clotting phenomena and right ventricular failure. Beyond outcomes, the literature is limited in the identification of pre-operative factors that drive lower than expected LVAD implant rates in this population. More focused research is needed to define the disparities in advance heart failure therapy delivery in women and other underserved populations. Women represent ~30–50% of patients with stage D heart failure , 2, but The epidemiology of heart failure in women varies significantly from that of men and, therefore, disparities in the treatment of advanced heart failure are frequently attributed to distinct biologies. While the lifetime risk of heart failure is similar in males and females , heart fThere have been two large analyses of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data that specifically address sex differences in utilization of LVAD therapy , 8. BothVentricular assist devices improve survival, functional status and quality of life. Although women in the greater heart failure community tend to have better survival, women report worse quality of life compared to age and ejection fraction matched male counterparts . While iThere is a paucity of data to help assess potential sex differences in decision making at the clinician or system level. It is known that females are less likely to receive temporary mechanical circulatory support in the setting of cardiogenic shock (OR = 0.76); this is also true of black patients and those insured by Medicare and Medicaid . An addiSex specific patient related treatment preferences may also contribute to differences in delivery of advanced heart failure therapies. Females have been shown to be less willing to undergo heart transplantation due to self refusal . AdditioOutcomes following durable LVAD implantation have improved over time with trends following device innovation and market approvals. LVAD therapy outcomes are frequently stratified by device era, with distinction between the early pulsatile flow devices (pre 2008) and more modern continuous flow devices (post 2008) corresponding to regulatory approval of the Heartmate II for destination therapy. A further distinction of the continuous flow era can be made between continuous flow design including axial devices  and centrifugal devices , with the regulatory approval of the Heartware HVAD for BTT in November 2012. This is particularly pertinent given a demonstrated era effect in improved survival when stratifying implants prior to and post 2013, which favors the more recent era . Lastly,2. With FDA approval of the Heartmate II, an era of smaller and lighter continuous flow devices ; however, there was no discernable difference in the continuous flow era  . An INTEThere is a differential morbidity profile following VAD implantation in females largely attributable to bleeding, thromboembolic phenomena and right ventricular failure. The origins of dysregulated coagulation in females have been explored through a broad range of investigations, including estrogen effects on clotting factors, sex differences in pharmacokinetics and dynamics of anticoagulants, as well as lower pump speeds, particularly in the era of the Heartmate II.Females who undergo LVAD implantation are at higher risk of neurologic events than their male counterparts. Early data with the Heartmate II highlighted an increased risk of hemorrhagic, but not ischemic stroke in females  inciden. More reA number of studies indicate that women are at higher risk of bleeding events both in the immediate post-operative period and more chronically while on anticoagulation therapy. A review of European Registry for Patients with Mechanical Circulatory Support (EuroMACS) data of 966 patients receiving a durable VAD (151 women) revealed that females were twice as likely as males to have a major bleeding event as defined by INTERMACs adverse event definitions. This applied for the first 30 days of post-implant period and also identified twice as many bleeding events per patient year compared to males . A singlRight ventricular failure is more common in women potentially due to a greater occurrence of non-ischemic cardiomyopathy, later presentation of disease, and higher incidence of arrhythmias . In a syWomen reflect a minority proportion of patients receiving advanced surgical heart failure therapies. There is a discrepancy between the high burden of heart failure in females and the number of females who ultimately receive LVAD therapy. Females who present for advanced heart failure therapies have a disparate preoperative profile compared to male counterparts, including the very nature of the underlying heart disease and associated comorbidities. Additionally, sex differences in pre-implant factors such as candidacy for transplantation and decision making at the patient, physician, and systems level may impact presentation for surgical evaluation and patient willingness to accept a device when offered. Much of what is known about LVADs in females with advanced heart failure is derived from the endpoint of device delivery, particularly at the clinical trial level; female sex has been associated with a historically higher rate of mortality and higher incidences of stroke, bleeding, and right ventricular failure following implant. While the representation of females within VAD study cohorts has increased with advances in technology, heart failure therapy and device trials overall continue to underrepresent females, with participation by females far lagging prevalence of the disease by 0.55:1.0 . Newer dThe treatment algorithm connecting a woman in the community with heart failure with successful LVAD implantation is complex. Patients with heart failure should be appropriately identified, medically managed, referred for surgical evaluation and ultimately undergo treatment. There is a critical knowledge gap in understanding the true number of females who could be eligible for or benefit from advanced heart failure therapies out in the community. Our current understanding of advanced heart failure care in females mainly reflects the outcomes of those patients who were able to obtain mechanical support or heart transplantation. To address disparities in access to care, we should understand the processes of advanced heart failure diagnosis, medical management, referral for surgery, and surgical decision making, as well as how each of these processes may be uniquely influenced by sex . DevelopKJ-U, AR, KK, SC, JH, FP, and PT contributed to conception and design of the review. KJ-U wrote the first draft of the manuscript. KJ-U, FP, and PT wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study was partially supported by the National Institutes of Health grant HL164416 awarded to PT.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.


For more than a century, experimental and clinical studies have implicated a critical role of the autonomic nervous system in regulation of cardiovascular function in health and disease. In recent years, there has been increasing attention to the possibility of applying autonomic interventions to address the challenging problem of alleviating morbidity and reducing mortality in patients afflicted with heart failure (HF) with reduced left ventricular ejection fraction (HFrEF). This is an important public health problem throughout the world since more than 26 million people are affected (doi: 10.15420/cfr.2016:25:2), and, in the United States alone, HF is a major cause of death resulting in >377,000 deaths annually (doi: 10.1161/CIR.0000000000001052).The prospect of applying chronic vagus nerve stimulation (VNS) to improve HF symptoms and status has been the focus of intensive study because of extensive preclinical and clinical evidence of its potential for cardioprotective actions. An attractive consideration of chronic VNS is its well-established safety profile and tolerability, determined in the treatment of >120,000 individuals with chronic epilepsy or depression, which has been under study for more than three decades. In this experience, it has been shown that chronic VNS in patients with pharmacoresistant epilepsy can safely reduce cardiac electrical instability and improve autonomic function.Chen et al.).The putative mechanistic bases for cardioprotection by chronic VNS as revealed by preclinical studies are multifold. Evidence of rich cholinergic innervation of the atrioventricular node and ventricular conducting system has been provided not only in widely studied canine models but also in human subjects. Multiple modes of action underlie the bases by which chronic VNS can prevent life-threatening arrhythmias including ventricular fibrillation. Among the most critical influences is antagonism of cardiac sympathetic nerve tone. Elegant studies of skin sympathetic nerve activity have shown that VNS is capable of containing adrenergic inputs to the heart  and cardiac antiapoptotic effects. Improvement in autonomic balance as assessed by heart rate variability (HRV) and baroreceptor sensitivity (BRS) by heart rate turbulence measurement has been documented . Overall, this suite of influences has been shown to improve both cardiac mechanical function and cardiac electrical stability as assessed by measures such as T-wave alternans and T-wave heterogeneity.The articles in the current research topic reviewed the main candidate effects for the protective action of VNS in the treatment of heart failure. Among the most significant are anti-inflammatory actions involving VNS-mediated decreases in circulating cytokines and augmentation of nitric oxide expression . The main apparent distinctive feature of ANTHEM-HF was use of the neural fulcrum to ensure appropriate titration of stimulation intensity that demonstrated efferent autonomic engagement in individual patients. This approach is reminiscent of the historical rationale used in pharmacologic therapy, specifically, “to administer the right drug, to the right patient, by the right route, at the right time, in the right amount, for the right duration” (doi: 10.1177/106002809002400615).Schwartz and colleagues (doi: 10.1016/j.ejheart.2008.07.016. PMID: 18760668) are to be credited for taking a critical step of conducting the first-in-man proof of concept investigation in patients with HF. Their study demonstrated that VNS improved HF symptoms and decreased left ventricular end systolic volumes. Importantly, the patients experienced relatively minor adverse effects of chronic VNS that tended to resolve over time, similarly to patients with epilepsy. Early clinical studies using VNS appeared promising; however, the larger INcrease Of VAgal TonE in Heart Failure (INOVATE-HF) trial and Neural Cardiac Therapy for Heart Failure Study (NECTAR-HF) were neutral with respect to the primary clinical endpoints. The only sizeable study with definitively favorable results has been the Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure (ANTHEM-HF) Pilot study .In support of the view that appropriate VNS intensity and protocol are essential is the fact that the ANTHEM-HF Pilot study resulted in multiple long-lasting benefits of chronic VNS on cardiac electrical stability and mechanical function in patients with HFrEF for more than 3 years. Specifically, there were progressive improvements in HRV, BRS, cardiac electrical stability as assessed by T-wave alternans and T-wave heterogeneity, and reduction in incidence of nonsustained ventricular tachycardia. Concurrently, there were significant improvements in left ventricular ejection fraction (LVEF), 6-min walk tests, and NYHA Class. It is noteworthy that the NYHA Class was improved in 96% of subjects. Furthermore, durable cardioprotective effects in terms of autonomic engagement and heart rate responsiveness to VNS were also observed in 15 patients enrolled in the ANTHEM-HF Pilot Study for an additional 2 years . The projected enrollment is 500 to 1,000 patients. The study design utilizes an adaptive, open-label, randomized controlled protocol. This investigation draws on insights derived from prior studies that optimized VNS dose, stimulation parameters, and selection of appropriate patients, together with a novel adaptive approach for guiding sample size, as allowed by the new United States Food and Drug Administration Breakthrough Device Program.Based on the sizeable body of evidence provided by prior preclinical and clinical studies, the Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction (ANTHEM-HFrEF) Pivotal Study (NCT03425422)  has been launched , “it is instructive to recall that cardiac resynchronization therapy, which is now a class I indication in HF patients, took over two decades to evolve from a concept in animal models to widespread clinical application.” The ANTHEM-HFrEF Pivotal Study could accelerate this timetable, given that the first-in-man study of VNS for HF was published in 2008.


To investigate whether recombinant human erythropoietin (rHuEPO) injections during an altitude training camp impact heart function.Thirty (12 women) moderately trained subjects stayed at 2320 m altitude for 4 weeks while training. Subjects were randomized to placebo  or rHuEPO (20 IU/kg body weight) i.v. injections. Transthoracic echocardiography imaging was acquired 3 days after arrival to altitude and prior to the first placebo or rHuEPO injection as well as one day after the last rHuEPO injection three weeks later.rHuEPO did not alter cardiovascular morphology parameters, systolic or diastolic function. In the placebo group, altitude exposure improved left ventricle (LV) systolic function due to an increased twist angle but rHuEPO had no additional effects. Pulmonary arterial systolic pressure was unaffected in either group. Notably, rHuEPO hampered LV untwist rate without affecting LV early filling.rHuEPO provided during mild altitude exposure does not cause any major effects on heart function. The observed alteration in LV untwist induced by rHuEPO is unlikely to have a meaningful clinical effect.Trial Registration Registered on www.clinicaltrials.gov (NCT04227665).The online version contains supplementary material available at 10.1186/s40798-022-00531-x. Recombinant human erythropoietin (rHuEPO) administration during an altitude training camp does not clinically compromise cardiac function.While rHuEPO may alter left ventricle mechanics, this is likely due to a secondary response of its haematological effects.Human sea-level residents frequently travel to altitude for recreational and work purposes . In addiEPOR are also expressed outside the hematopoietic system, including in cardiomyocytes , 9. In rHuman heart adapts its function and mechanics to preserve systolic function during altitude exposure. For instance, after several days to altitude exposure, there is a reduced stroke volume –19 whichwww.clinicaltrials.gov (NCT04227665) and performed in accordance with the Declaration of Helsinki.Thirty  moderately trained, sea level inhabitants and non-smoking subjects were recruited. None of the participants had been exposed to an altitude above 1,000 m for > 1 month or donated blood for > 3 months before the study. All the subjects gave their written informed consent to participate in a randomized, single-blinded, placebo-controlled study approved by the ethics committee of Copenhagen, Denmark (H-17036662), registered on n = 12, 5 females), consisting of intravenous injections of 20 IU × kg bw−1 epoetin alpha , or to placebo  consisting of intravenous injections of ~ 0.3 mL isotonic saline . Participants wore a blindfold during injections to maintain blinding. Treatment started on the third day following arrival to altitude and was given every second day for three weeks, resulting in a total of eleven injections. Post-data were collected a day after the last injection. In this period, subjects trained daily including both resistance and endurance training. Details of the training program are reported elsewhere [The present study was performed during the altitude trial arm of a larger study which aimed to determine biological markers for detection of blood doping at altitude . Pre-datlsewhere .Transthoracic echocardiography was performed using a commercially available system  with a X5-1, 1 to 6-mHz phased-array, transducer. Images were obtained from parasternal short-axis and apical four-chamber views with 2D frame rates of 60 to 100 frames/s and tissue Doppler frame rates > 100 frames/s. Off-line data analysis  was performed by a cardiologist blinded to group allocation.Two-dimensional (2D), pulsed-Doppler, and colour tissue Doppler imaging were performed from parasternal short-axis. Images were obtained at the same frame rate to facilitate subsequent LV torsion and rotation analysis. The LV ejection fraction was calculated offline from 3D images . We defined LV length as the end-diastolic length from the mitral valve hinge point plane to the most distal endocardium at the LV apex and it was measured in the apical 4-chamber view. Pulsed-wave Doppler images were used to measure aortic valve opening/closure and mitral valve opening. Isovolumetric relaxation time (IVRT) was calculated as the difference between mitral valve opening and aortic valve closure. The left and right ventricular outflow tract diameter was measured from the parasternal long-axis view and was used to calculate stroke volume as previously , 25. CarMyocardial deformation was measured as previously described . Global t test for independent samples (rHuEPO vs. placebo). Statistical significance was set at P < 0.05 and we considered P < 0.08 as a statistical tendency. Analyses were performed using SPSS version 20. Additional file Data are reported as mean ± standard deviation. Normality was evaluated by a Kolmogorov–Smirnov tests. Data were analysed using a 2 (Groups) × 2 (Time) repeated measures ANOVA, within subject design. When a significant interaction was reported, the model was adjusted with gender as covariate. Significant interactions were further evaluated by Student’s Heart rate, diastolic blood pressure and mean blood pressure were reduced in both placebo and rHuEPO groups following 3 weeks of moderate altitude exposure, whereas systolic blood pressure remained unchanged Table . No timeTable p = 0.077) towards an increase in the S′ wave in the lateral tricuspid annulus  to decrease We found that late filling (peak A wave) was reduced by moderate altitude exposure while left ventricle early filling was unchanged (peak E wave) Table . In thisentclass1pt{minimaentclass1pt{minimaentclass1pt{minimap = 0.039) when the model was adjusted for the gender of the subjects , immediately before rHuEPO and placebo injections. This is of importance as most of the acute effects of hypoxia on the heart are evident within the first 4 days following exposure . For insIn addition, PAAT, an accurate marker of pulmonary arterial systolic pressure , was unaThe store and release of energy through elastic components are a key process linking systole and diastole. The diastole phase consists of two phases: initially, due to the stored energy of the elastic component, the pressure gradient between the atria and the ventricles is high and ventricular filling is rapid (the phase of rapid early filling). Under normal circumstances, about 70% of ventricular filling occurs during this phase. As diastole progresses, ventricular pressure rises and the rate of filling slows (i.e. diastasis phase). The final ~ 25% of filling during ventricular diastole results from atrial contraction  .Untwisting occurs during the diastole phase of rapid early filling and is directly influenced by the relaxation of cardiomyocytes and the release of potential energy stored during systole . InteresOn the other hand, rHuEPO is better known for its effect outside the cardiovascular system in humans. For instance, increased red cell production, angiogenesis, myogenesis, shift in muscle fibre types, and oxidative enzyme activities in skeletal muscle have been reported  that mayFinally, it has been reported that untwist velocity increases immediately in response to altitude exposure, an effect that is maintained for 4 days, but which is normalized to sea levels after 6 days . Thus, tHere, we show that low dose rHuEPO injections provided during mild hypoxic exposure do not cause any major effects on heart function. Thus, no immediate health hazards are obvious for athletes training at altitude and no obvious beneficial effects of mild hypoxic exposure and/or rHuEPO treatment can be expected as evaluated on a young symptom free healthy population.Additional file 1. Supplementary Figure 1. Untwist velocity in response to mild altitude and rHuEPO injections. p values denotes post hoc test (Student´s t) analysis following a significant 2 (Groups) x 2 (Time) repeated measures ANOVA, within subject design corrected and corrected for Gender (p = 0.039 see main text).