Left ventricular ejection fraction (LVEF) and end-systolic volume (ESV) remain the main imaging biomarkers for post-acute myocardial infarction (AMI) risk stratification. However, they are limited to global systolic function and fail to capture functional and anatomical regional abnormalities, hindering their performance in risk stratification.This study aimed to identify novel 3-dimensional (3D) imaging end-systolic (ES) shape and contraction descriptors toward risk-related features and superior prognosis in AMI.A multicenter cohort of AMI survivors  who underwent cardiac magnetic resonance (CMR) at a median of 3 days after infarction were considered for this study. The clinical endpoint was the 12-month rate of major adverse cardiac events , consisting of all-cause death, reinfarction, and new congestive heart failure. A fully automated pipeline was developed to segment CMR images, build 3D statistical models of shape and contraction in AMI, and find the 3D patterns related to MACE occurrence.P < 0.001); and 3D contraction to LVEF  in MACE occurrence prediction. They also contributed to a significant improvement in a multivariable setting including CMR markers, cardiovascular risk factors, and basic patient characteristics . Based on these novel 3D descriptors, 3 impairments caused by AMI were identified: global, anterior, and basal, the latter being the most complementary signature to already known predictors.The novel ES shape markers proved to be superior to ESV (median cross-validated area under the receiver-operating characteristic curve 0.681 [IQR: 0.679-0.684] vs 0.600 [IQR: 0.598-0.602]; The quantification of 3D differences in ES shape and contraction, enabled by a fully automated pipeline, improves post-AMI risk prediction and identifies shape and contraction patterns related to MACE occurrence.  Preventive and personalized medicine is crucial to improving both the efficiency and efficacy of health care systems.,,Cardiac magnetic resonance (CMR) imaging has proven to be uniquely suitable to assess morphological and functional myocardial alterations, including left ventricular (LV) remodeling, which is central to AMI early prognosis prediction.,,LVEF and ESV are limited to global systolic function and fail to capture functional and anatomical regional abnormalities.The present study aimed to disentangle ESV and LVEF into 3D shape and contraction with the use of only standard CMR short-axis stacks (SAx) to: 1) gain a better understanding of how 3D remodeling patterns modulate risk and the interplay between macro-remodeling and microdamage; and 2) improve AMI risk stratification. We present a fully automated shape analysis pipeline including state-of-the-art artificial intelligence and 3D meshing and its application on a large multicenter population including ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) patients.NCT00712101) and TATORT-NSTEMI .,Our retrospective population consisted of 1,235 AMI survivorsAIDA-STEMI and TATORT-NSTEMI were registered with ClinicalTrials.gov, were approved by the institute ethics committees, and complied with the Declaration of Helsinki, including written informed consent. Data supporting our findings are available on reasonable request.,The same standardized protocol, including electrocardiography-gated balanced steady-state free precession sequences and T1-weighted late gadolinium enhanced images, was followed for all patients with AMI on 1.5-T or 3.0-T clinical scanners.,,The 12-month rate of MACE, consisting of reinfarction, new congestive heart failure, and all-cause death, was the predefined clinical endpoint of the study as detailed previously.The LV myocardium was segmented in the SAx images, and 2 personalized 3D LV meshes were built for each patient: at end-diastole (ED) and at end-systole (ES). The displacements between corresponding points in them constituted the 3D contraction. 3D shape and contraction descriptors were obtained by unsupervised construction of statistical shape models and used as potential predictive biomarkers. The process  was full,A 2-step deep learning approach was applied to segment the LV myocardium, based on a UNet architecture with enhanced preprocessing,The construction of 3D meshes from segmentation contours used a solution based on smooth cubic Hermite interpolation, which was shown to be accurate and robust concerning SAx slice misalignment and segmentation errors and fully described in Lamata et al.The direct analysis of the 3D meshes, discretized into 2,450 nodes with their corresponding 3D spatial coordinates, is impractical and ill posed. This motivates the use of principal component analysis (PCA) for dimensionality reduction.Three statistical shape models were built with this PCA technique, studying the 3D shape at ED and at ES, and the displacement between them (contraction). PCA coefficients of ED were found to contain no predictive value and are therefore not reported.The relevant PCA modes to predict MACE were found by a stepwise multivariable Fisher linear discriminant analysis (LDA), as detailed below. The search was performed on the ES shape and on the contraction modes needed to reconstruct 95% of the total variance of the population. This selection was further refined with another LDA applied on the combination of ES and contraction-significant modes found in the previous step.The predictive value of the novel ES shape and contraction PCA modes was evaluated against standard clinical biomarkers and in combination with them. Conceptually, ES and contraction PCA modes are the 3D extension of the ESV and LVEF biomarkers, and a first test compared them. Multivariable combinations were next investigated, considering only CMR biomarkers and all the clinical variables of the study together.P value threshold was met by all of them. Significance in the LDA was approximated as significance in the generalized linear binomial sigmoid regression model. To account for both specificity and sensitivity and class imbalance, the performance of the resulting configurations was assessed via area under the receiver-operating characteristic curve (AUC) for binary classifications and by concordance index (C-index) for time-dependent curves.Comparisons were based on the prediction performance resulting from both a multivariable LDA (binary classification of MACE occurrence at 12 months) and a multivariable Cox analysis (time to MACE). A backward stepwise strategy  and cross-validation . To further strengthen this generalization, an additional experiment trained the models only on AIDA-STEMI patients and tested them on the TATORT-NSTEMI independent cohort . A repro,The variables of the study  are described according to MACE occurrence. Continuous variables are presented as median (IQR), because they were not normally distributed in a Shapiro-Wilk test except for the modes of variation (which are gaussian distributed by definition). Categoric variables are presented as frequencies and percentages. The MACE and No MACE distributions, as well as the cross-validated AUC distributions, were compared by means of the nonparametric Wilcoxon rank sum test. Univariate Cox regression analyses were also performed. HRs, 95% CIs, and the predictor significance are presented in the results. All analyses were implemented in Matlab R2019b. The study follows the guidelines of the Transparent Reporting of Multivariable Prediction Model for Individual Prognosis or Diagnosis  and the ,,,A total of 1,021 patients with AMI  out of the initial 1,235 cohort had both original CMR scans and 12-month follow-up data available and were included in this study .,,CMR and baseline clinical characteristics are described in rs) between the volumes calculated from automated and manual segmentations were 0.916, 0.919, and 0.842 for ESV, EDV, and LVEF, respectively. The median distances between mesh surfaces and contours were 0.981 mm (IQR: 0.806-1.22 mm) for ES and 1.02 mm (IQR: 0.828-1.31 mm) for ED. The rs coefficients between the manual volumes and those integrated from the mesh were 0.905, 0.914, and 0.792 for ESV, EDV, and LVEF, respectively. The resulting LVEF calculated from the meshes was negative for 4 patients because of noise in the midventricular segmentation that led to an incorrect phase selection. They were excluded from the statistical analysis  and 0.975 (IQR: 0.959-0.982) for LV epicardium and endocardium, respectively. The Spearman correlation coefficients  compared with manual contours  of endpoint prediction from 0.60 to 0.68 (P < 0.001) with respect to ESV; the LDA on 3D contraction, described by the contraction modes 3, 5, and 16, increases from 0.68 to 0.72 (P < 0.001) compared with LVEF  and including cardiovascular factors and basic patient characteristics (AUCk = 0.747) led to a further improvement compared with the clinical baselines (P < 0.001). Similar results were obtained for C-indexes  combined AI and computational anatomy technologies to develop a fully automated pipeline that segments the cine CMR SAx stack and identifies the 3D signatures of AMI that predict risks along the first year of follow-up; 2) identified these LV shape and contraction macrofeatures related to AMI prognosis and built a 3D reference atlas from more than 1,000 AMI patients; and 3) proved that a 3D enhancement of ESV and LVEF not only outperforms the standalone versions, but also contributes to a significant overall risk prediction improvement in a multivariable setting including CMR markers, cardiovascular risk factors, and basic patient characteristics.Our automated method takes a CMR stack, segments the LV, and summarizes its shape and contraction related to AMI into 6 biomarkers. It reduces the time of the analysis to seconds, removing the burden of manual segmentations. The mesh-fitting stepR2 = 0.987; ESV: R2 = 0.990) and confirms a good reproducibility of the method (multivariable: R2 = 0.901)   and 8, wAs a result of the automated shape analysis, we have built a 3D LV reference atlas from more than 1,000 patients with AMI that captures the average shape and contraction after infarction alongside the main variations (PCA modes). These data and the resulting risk models, which have been made publicly available,LVEF and ESV are the most established markers for postinfarction risk assessment. Although there are data suggesting that these parameters can be fully automatically determined with the use of commercially available software,Furthermore, these 3D patterns are complementary to the other variables included in the study , as evid,,rs = 0.868), C3 with LVEF (rs = −0.563), and ES6 with ES myocardial thickness.,,The severity of the infarct is associated with morphological and functional alterations, and certain acute changes have proven to be important to AMI prognosis, but their interplay in modulating MACE occurrence remains unsolved.The derived risk score model, however, does not include the contraction patterns C2 and C14, which could be interpreted as related to injury in the left circumflex and right coronary arteryrs = 0.461) and MVO (rs = 0.345). Risk-related shape and contraction variations (except for C16) are also significant in stratifying IS and MVO into low vs high myocardial damage, using the median values of the AMI population as threshold . This enables for fair and direct comparisons between traditional metrics  and their 3D versions. Future work will explore the time dimension and benefit from automated segmentations and 3D reconstruction across the cardiac cycle, presumably finding an even superior marker. The temporal CMR strains, reported to be prognostic in postinfarction management,The PCA geometric features are limited to the gaussian assumption, yet they satisfactorily cover the observed variability in the cohort. Although other approachesCMR long-axis views were excluded from the 3D shape regression for the sake of simplicity, which, although it was not evidenced in our results, may result in shape-lengthening noise. Finally, the results are limited to patients with AMI who can undergo a CMR scan.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: This large-size multicenter CMR study identifies the 3D LV patterns related to postinfarction risk and proves their superior prognostic information compared with the most-established predictors, EF and ESV. Moreover, it highlights the value of multivariable CMR models in AMI stratification and further supports the feasibility of fully automated CMR analysis.TRANSLATIONAL OUTLOOK: The study demonstrates the potential of 3D computational models to improve myocardial infarction management. This is attained by building a refined understanding on the functional and structural interplay that modulates risk, and by bringing the robustness of state-of-the-art tools, which ease the clinical workflow and pave the road toward multivariable models and CMR imaging use. To further accelerate this vision and facilitate future contributions, the 3D shape and contraction atlases and shape models resulting from the study have been made publicly available.This multicenter CMR study evidences the prognostic value of novel LV 3D shape and contraction metrics in AMI risk assessment. Besides, it further proves the feasibility of fully automated CMR analysis and the significance of multivariable CMR models in AMI stratification.This work was supported by the EU’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie (ga 764738), the German Center for Cardiovascular Research, the British Heart Foundation , and the Wellcome Trust (209450/Z/17). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Clinically significant tricuspid regurgitation (TR) is common and associated with excess mortality. At the same time right ventricular (RV) failure is a complex clinical syndrome that results from many causes, but is often associated with long-term prognosis. Whilst results of isolated tricuspid valve (TV) surgery are often unsatisfactory and limited by the prohibitive risk of most patients, the recent development of percutaneous recovery techniques has opened new scenarios. In consideration of the complexity of the mechanisms that lead to right heart failure and RV dysfunction it is important to understand the real advantages that percutaneous TV treatment can offer, more specifically the effect of TR reduction on RV remodeling in the setting of functional tricuspid regurgitation (fTR). Functional tricuspid regurgitation (fTR) is the most common cause of TR as it usually comes as a result of annular dilation and leaflets tethering caused by right ventricle (RV) enlargement and dysfunction due to pressure/volume overload related to left-sided heart disease (ventricular fTR) or atrial fibrillation  , 2. It hAs surgical repair tipically addresses annular dilatation, it is still unclear whether the same assumptions can be made for percutaneous treatments, in particular for those not directly acting on annulus size. In addition, scarce data is available about the effect of tricuspid treatment on RV function as assessed by advanced imaging techniques.Aim of the present review is to evaluate the effect of percutaneous leaflet repair on RV function and size in the subgroup of patients with fTR.FTR usually develops due to structural alterations in right atrial and/or ventricular myocardial geometry, leading to tricuspid annulus dilation and/or leaflet tethering, both associated with impaired leaflet coaptation. This is by far the most common cause of TR in adults, as shown by echocardiographic studies in which over than 90% patients with severe TR had a functional etiology , 8. Mult1) patients without left-sided heart disease and without pulmonary hypertension, in whom significant fTR may appear attributable to right atrial dilation and atrial fibrillation, whereas the RV dimensions and function are usually within the normal values;2) patients with left-sided heart disease and pulmonary hypertension, in whom TR is associated with various grades of RV dilation and dysfunction, usually related to myocyte loss and fibrosis that would finally affect prognosis.While the benefit of tricuspid repair looks high in the former group, it is still not clear to what degree of RV dysfunction this process is reversible. In a study by Topilsky et al. , idiopatTricuspid transcatheter edge-to-edge repair using the TriClip™  or leaflet approximation with the PASCAL systems  are the currently available systems for percutaneous tricuspid repair. In the core lab-adjudicated TRILUMINATE study, percutaneous tricuspid repair in 85 prospectively enrolled patients  was associated with a durable reduction to moderate TR or less in 71% at 1 year , 17. IntEvaluation of RV size and function is universally considered more complex than the one of left system. The biomechanics of the RV are significantly different from those of the LV and are optimized to deal with changes in volume load and to work at low pressure. This complex biomechanical construct and the change in relative components of radial function and longitudinal function with loading adds to the complexity in overall assessment of RV function .Among all possible imaging modalities, echocardiography and cardiac magnetic resonance (CMR) should be considered as first-line tools to assess RV function changes over time , 21.Echocardiography is by far the most common way to evaluate RV dimensions and function but technical issues are well known. Quantitative assessment of the RV by 2D transthoracic echocardiography is challenging due to its complex asymmetric geometry that leads to incomplete visualization in a single projection and lack of precise anatomic landmarks. Differently from LV, there are no geometrical assumptions for end-diastolic volume (EDV) and end-systolic volume (ESV) measurements. In addition, 2D echocardiography diameters of the RV may significantly vary just with minor rotation of the probe due to the lack of a precise and specific landmark, leading to a significant under- or over- estimation of RV size.Evaluation of RV size and function is usually multiparametric and different echocardiographic techniques can be used. However, this usually leads to data fragmentation, thus preventing inter-study correlations. 3D echo can overcome these limitations but requires specific reconstruction software, it's time consuming and is limited by acoustic impedance.3D echocardiography has demonstrated excellent correlation with CMR for the calculation of RV volumes and ejection fraction with a slight systematic underestimation of EDV and ESV but no difference in terms of RV ejection fraction .CMR, even if limited by availability and costs, is considered the gold standard for evaluating RV volume, mass and function due to the volumetric acquisition providing excellent myocardial definition and tissue characterization. CMR permits direct EDV, ESV and EF measurement without geometrical assumption. Atrial arrhythmias might interfere with image acquisition and the presence of intrathoracic prosthetic material  in certain cases can lead to significant artifact making CMR images uninterpretable.CMR not only allows precise evaluation of RV ventricular volumes and function but is able to calculate both left and right actual forward stroke and regurgitation volumes.Atrial fTR and ventricular fTR usually show two different remodeling patterns. The atrial fTR is linked with aging, atrial fibrillation, diastolic dysfunction, associated with a predominant atrial and annular dilatation with the latter as the predominant mechanism of TR. RV dilation in these cases is usually mild and limited to the basal segment.Ventricular fTR has a different remodeling pattern with significant RV enlargement, less prominent annular dilatation and marked leaflets tethering as the leading mechanism of regurgitation. It is often due to left-sided ventricular or valve diseases, primary RV dysfunction as a consequence of RV infarction or cardiomyopathy, or pulmonary hypertension.Residual TR and RV reverse remodeling after cardiac surgery are sensitive predictors of long-term prognosis  after suAlthough available data is scarce, it seems that different degrees of reverse remodeling are linked to different etiologies of TR and degree of RV remodeling and dysfunction at the time of surgery. Several different papers showed a positive reverse remodeling after tricuspid surgical repair during mitral valve surgery , pulmonaSurgical series should be considered as a reference guide to predict the effect of percutaneous repair on RV remodeling. Data derived from the Triluminate study  shows siChanges in RV loading condition and forward stroke volume lead to an improvement in left ventricular (LV) hemodynamic performance through an increase in LV preload documented by an increase of EDV and EF in the context of the so called “chronic latent LV under filling” . In thisFinally, volume overload determined by severe TR is a major determinant of right atrium remodeling resulting in structural, electrical, or metabolic changes often leading to chronic atrial fibrillation . IrrespeIn conclusion, available preliminary data indicate an initial efficacy of percutaneous tricuspid repair on RV remodeling, with possible benefits to both ventricles. However, these results need confirmation from further and longer studies able to identify the subgroups of patients who may benefit more from the procedure.AA contributed to conception and design of the study. RN, AS, and FC wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Patients with continuous flow ventricular assist devices (CF-VAD's) in the systemic ventricle (left ventricle or single ventricle) often have no palpable pulses, unreliable pulse oximetry waveforms and non-pulsatile arterial waveforms despite hemodynamic stability. When circulatory decompensation occurs, standard indicators to begin cardiopulmonary resuscitation (CPR) which are used in other pediatric patients  cannot be applied in the same fashion. In this population, there may already be pulselessness and development of bradycardia in and of itself would not trigger chest compressions. There are no universal guidelines to dictate when to consider chest compressions in this population. As such, there may be a delay in decision-making or in recognizing the need for chest compressions, even in patients hospitalized in intensive care units (ICU) and cared for by experienced staff who perform CPR regularly. We present four examples of pediatric cardiac ICU patients from a single center who underwent CPR between 2018 and 2019. Based on this case series, we propose a decision-making algorithm for chest compressions in pediatric patients with CF-VADs in the systemic ventricle. The implantation of ventricular assist devices (VADs) in pediatric patients has become relatively widespread and has increased with time over the past decade –3. AccorWhile Pedimacs and other registries –6 collecPediatric patients with continuous flow ventricular assist devices (CF-VAD's) in the systemic ventricle (left ventricle or single ventricle) often have no palpable pulses, unreliable pulse oximetry waveforms and non-pulsatile arterial waveforms despite hemodynamic stability. When circulatory decompensation occurs, standard indicators to begin cardiopulmonary resuscitation (CPR) which are used in other pediatric patients   cannot bWe present four cases of pediatric patients with CF-VADs from a single center who underwent in-hospital CPR between 2018 and 2019. Based on this case series, we propose a decision-making algorithm for chest compressions in pediatric patients with CF-VADs in the systemic ventricle.2) male with muscular dystrophy and dilated cardiomyopathy, who underwent placement of a HeartMate-3™  left ventricular assist device (LVAD) as destination therapy. On post-operative day 10, he developed significantly decreased VAD flows associated with worsening right ventricular function and the development of pericardial tamponade. He was initially planned for an urgent pericardiocentesis. Asystole occurred upon induction of anesthesia, and chest compressions were initiated shortly after, as the VAD flows declined. He instead underwent an emergent subxiphoid pericardial window. Duration of chest compressions was 15 min. There was evidence of significant neurologic injury after the event, which led to withdrawal of life support.Patient #1 was a 16-year-old, 70 kg (1.8 m2) girl with congenital heart block who developed pacemaker-induced cardiomyopathy. As a bridge to heart transplant, she underwent placement of a Jarvik 2015 LVAD  in addition to a PediMag™  right ventricular assist device (RVAD). On post-operative day 6, while mechanically ventilated, there were low-flow alarms from her RVAD. It was quickly noted that she had had accidental disconnection of her RVAD inflow cannula. This quickly resulted in significant blood loss and hypotension. Her RVAD cannula was quickly reconnected and pump speed resumed. She received 4 min of CPR prior to resumption of full flows. She suffered no neurologic injury and ultimately underwent heart transplantation six months after VAD placement.Patient #2 was a 3-year-old, 14 kg (0.56 m2) male with dilated cardiomyopathy who underwent placement of a HeartMate-3™ LVAD. On post-operative day 9, he was noted to have rising central venous pressures (CVP) and elevated lactate levels, as well as a drop in hemoglobin. He soon developed altered mental status, hypotension, and low-flow alarms from his VAD. Over the course of minutes, he had progressively lower flows. When flows dropped below 0.5 L/min, chest compressions were initiated. He received 2 min of chest compressions, with simultaneous administration of an intravenous fluid bolus and a dose (0.01 mg/kg) of epinephrine. VAD flows were restored, as was mean arterial pressure (MAP). He underwent an emergent mediastinal exploration, which revealed hemopericardium and a hemothorax.Patient #3 was a 17-year-old, 110 kg (2.1 m2) female with dilated cardiomyopathy. She underwent placement of a HeartWare™ HVAD™  LVAD. On post-operative day 14, her VAD flows acutely dropped to 0.8 L/min, MAP dropped from 60 to 65 mmHg to <30 mmHg and she became suddenly unresponsive. Prior to this, she had been awake, alert, sitting up, receiving non-invasive mechanical ventilation. Chest compressions were initiated, immediately followed by the administration of an epinephrine dose (0.01 mg/kg) and an intravenous fluid bolus. After a 2-min cycle of CPR, VAD flows increased and MAP normalized. She was subsequently confirmed to have pericardial tamponade, and underwent mediastinal exploration with hematoma evacuation. On post-operative day 24, now sedated and intubated, this patient had another acute drop in VAD flow after administration of a fosphenytoin dose for new-onset seizures. VAD flows again dropped below 1 L/min, and MAP dropped below 30 mmHg. With this second event, mental status changes could not be assessed as she was receiving sedative infusions. She did not receive chest compressions. She was given a dose of epinephrine (0.01 mg/kg) and an intravenous fluid bolus. VAD flows and MAP normalized.Patient #4 was a 15-year-old, 53 kg  initially came to clinician attention due to low-flow alarms . In patiUsing the knowledge of sequence of events in these 4 cases, we created an algorithm to guide the decision about initiation of chest compressions in pediatric patients with CF-VADs in the systemic ventricle . We deciOur decision-making algorithm starts with a response to a low-flow alarm. We chose to start here since 3 out of 4 patients in our case series came to clinician attention due to low-flow alarms. Our algorithm is initiated once the indexed VAD flow falls below 1 liter per minute per square meter. We did not start with a patient symptom first , because in all of our 4 cases, the low-flow alarm preceded every symptom in drawing attention to the patient.We considered complete VAD failure and the absence of a palpable pulse to be a clear indication for chest compressions. In cases where there is VAD dysfunction but the presence of a pulse, we recommend that the decision to initiate chest compressions be based on poor perfusion associated with a heart rate <60 beats per minute, in alliance with the American Heart Association (AHA) pediatric basic life support guidelines .via intra-arterial catheter or non-invasively via the Doppler opening pressure (DOP). Confirmation of non-pulsatile flow prior to MAP measurement by cuff is important since the DOP may over-estimate the MAP and may more closely correlate with systolic pressure if the patient is pulsatile , followed by determination of mean arterial blood pressure (MAP). MAP measurement can be accomplished invasively ulsatile . The steulsatile .2) to < 20 mmHg (for intubated patients).Excessively high MAP's should be treated to restore flows. For low MAP's, we set cut-off points by weight, which we call the “drop-off MAP.” In those low-flow patients whose MAP's fall below the “drop-off MAP” cutoff, we propose that the decision point for initiation of chest compressions should be acute change in mental status (for non-intubated non-sedated patients) or a drop in invasive end-tidal carbon dioxide , clinicians may be uncertain about what cutoff points should trigger chest compressions, or whether to use inotropes alone.Garg et al. reviewed a series of adult patients with continuous-flow left ventricular assist devices (LVADs) who underwent in-hospital CPR, and compared them to patients without VADs at the same hospital who suffered in-hospital cardiac arrest. They found a statistically significant difference in time to initiation of chest compressions, with the VAD patients experiencing a delay in initiation. They attributed this delay to clinician uncertainty about when to start compressions in this group of patients who are pulseless at baseline. They coined the term “hypotensive electrical activity” (HEA), and created an algorithm to establish cut-off points beyond which chest compressions should be initiated . YuzefpoSimilar to these adult cases, our pediatric cases involved clinician uncertainty about timing of initiation of chest compressions, leading to short delays in resuscitation. Our cases were from a pediatric cardiac intensive care unit at a single large tertiary center that provides a broad range of advanced cardiac therapies. Our proposed CPR algorithm for pediatric CF-VAD patients is written for hospitalized patients in intensive care units. This algorithm was presented several times before multidisciplinary groups for feedback as well as education.2. The published adult VAD CPR algorithms  remains a controversial topic. This is true even in adult medicine where it is more likely (than in pediatrics) that one blood pressure number chosen may apply to most patients. Harper et al., in an editorial in 2020, proposed a systolic blood pressure <50 mmHg as a trigger to initiate chest compressions in the anesthetized adult patient , data collation, creation of algorithm, and writing of manuscript. PY: editing of algorithm, review of literature, and review of manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Takotsubo cardiomyopathy (TTC) shows reversible hypokinesis in the left ventricular (LV) apical-half segment and hyperkinesis in the LV basal-half segment. However, the precise pathophysiological mechanism of TTC is unclear. Therefore, this study sought to clarify the nuclear characteristics, degree of myocardial damage, and serial change of TTC and rTTC using myocardial perfusion imaging.We performed myocardial perfusion scintigraphy in 28 patients  using Tc-99m sestamibi and assessed minimum percentage uptake (min-%-uptake), extent score (ES) and summed rest score (SRS) at acute and chronic phases.P  < 0.01; rTTC: 60 [55-64]% vs 77 [71-79]%, P < 0.01), as did the ES  and SRS .Min-%-uptake improved from the acute to the chronic phase (TTC: 54 [48-59]% vs 87 [81-90]%, Tc-99m sestamibi uptake was reduced in hypokinetic regions in the acute phase and improved in the chronic phase. TTC and rTTC may involve a reversible disorder of the myocardial cell membrane, mitochondria, and microcirculation.The online version contains supplementary material available at 10.1007/s12350-021-02755-y. Takotsubo cardiomyopathy (TTC), so-named for its resemblance to a Japanese octopus trap and also known as “broken-heart syndrome,” is accompanied by chest symptoms such as chest pain and shortness of breath following severe emotional or physical stress and changes to an electrocardiogram (ECG) similar to that for acute myocardial infarction Figure A. This d5The precise pathophysiological mechanism of TTC is unclear, but there are some hypotheses such as multivessel epicardial spasm,We performed myocardial perfusion scintigraphy using Tc-99m sestamibi for 2076 patients between April 2004 and March 2013 in our hospital. Thus, approximately 19% (392 patients) were diagnosed with cardiomyopathy, and 30% (119 patients) had takotsubo cardiomyopathy or its variant . Moreover, 24% (28 patients) with takotsubo cardiomyopathy or its variant underwent myocardial perfusion scintigraphy using Tc-99m sestamibi in the acute and chronic phase  , and in the chronic phase, SPECT was performed approximately one month after admission .We prospectively enrolled 20 TTC and 8 rTTC patients in our study, on whom we performed myocardial perfusion scintigraphy at the Hamamatsu Red Cross Hospital, Hamamatsu, Japan. Patients were diagnosed with either TTC or rTTC based on the Mayo Clinic criteria: transient hypokinesis, akinesis, or dyskinesis of the left ventricle; regional wall motion abnormalities extending beyond a single epicardial vascular distribution; the presence  of a stressful trigger; absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; new ECG abnormalities (either ST segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and the absence of pheochromocytoma or myocarditis.This study was conducted in accordance with the guidelines of the Declaration of Helsinki. However, because of the retrospective and observational nature of this study, the need for written informed consent was waived.All patients underwent a Tc-99m sestamibi ECG-gated SPECT (rest study only) in the acute phase after hospitalization and in the chronic phase approximately one month later. A dose of 740MBq Tc-99m sestamibi was administered intravenously to each patient, after which each of them received a light meal to improve Tc-99m sestamibi clearance from the hepatobiliary tract. One hour later, SPECT was performed using a digital gamma camera  equipped with low-energy, high-resolution collimators. Transaxial tomograms of 6 mm-thick sections were processed using the filtered back projection method with the Shepp-Logan filter. The data were reconstructed in the transaxial, short-axial, and vertical long-axial planes. Bull’s eye maps were generated from the short-axial planes. LV function was analyzed using the quantitative ECG-gated SPECT (QGS) software.The LV myocardium was divided into 17 segments on the Bull’s eye map. The Tc-99m sestamibi uptake in each segment was expressed as the percent uptake (%-uptake) in the region with the maximal Tc-99m sestamibi uptake (reference region). We defined the minimum-%-uptake (min-%-uptake) as the segments where the accumulation was the lowest in the acute or chronic phases Figure . The ext12The LV time-volume curve was automatically calculated using QGS software program. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and the LV ejection fraction (LVEF) were then derived from the curve. Next, the time-filling rate curve was computed from the first derivative of the time-volume curve (dV/dt). The peak ejection rate (PER) was defined as the minimum dV/dt value divided by EDV (per second). The peak filling rate (PFR) was defined as the maximum dV/dt value divided by EDV (per second). Finally, the one-third mean filling rate (1/3MFR) was calculated as the average of dV/dt values in the first third of the filling time (per second).P value < 0.05 was considered statistically significant. All analyses were performed using R v3.1.1 .Continuous variables were expressed as median (interquartile range). The Wilcoxon test was used for intragroup comparison between acute and chronic phases, and the Mann-Whitney test was used to compare the TTC and rTTC groups. All categorical variables were expressed as raw numbers and percentages and were analyzed using Fisher’s exact test. A two-tailed Baseline characteristics are shown in Table P = 0.12). The min-%-uptake in the chronic phase was significantly higher in the TTC than rTTC group . The ES did not differ between the groups during the acute and chronic phases. The SRS in the acute phase was significantly higher in the TTC than rTTC group . The LVEDV, LVESV, LVEF, PER, PFR, and 1/3 MFR did not differ between the groups during the acute and chronic phases . The min-%-uptake improved from the acute to the chronic phase     The LV function improved one month following hospitalization in both groups. (2) Myocardial perfusion scintigraphy revealed that min-%-uptake, ES, and SRS were mild to moderately reduced in the acute phase in both groups. (3) Min-%-uptake, ES, and SRS were normalized with progression from acute to chronic phase in both TTC and rTTC patients.Although rTTC is similar to TTC in its clinical course, it is thought to be a variant of TTC. In this study, the distribution of age and gender and the frequency of preceding stressful events in rTTC did not differ from those of TTC, demonstrating similarity between TTC and rTTC. The prevalence of such variants has previously been considered rare, but the reported number of TTC variants has increased in recent years.et al. reported that cardiovascular magnetic resonance imaging revealed that TTC showed four distinct patterns of regional ventricular ballooning: apical (82%), biventricular (34%), midventricular (17%), and basal (1%).Eitel Nuclear cardiology imaging has provided much information regarding the pathophysiology of TTC. Thallium chloride 201Tl) or Tc-99m sestamibi is used as a tracer for evaluating myocardial blood flow, the myocardial cell membrane, and mitochondrial function. Several studies have shown a decrease in tracer uptake during the acute phase of TTC, and its abnormality gradually improves in the subacute and chronic phases using Tc-99m sestamibi myocardial SPECT.1Tl or Tc18F-flourodeoxyglucose (FDG) has shown that glucose metabolism is also severely impaired while myocardial perfusion is almost normal.18123I metaiodobenzyl guanidine (MIBG) scintigraphy can assess myocardial sympathetic nerve terminal activity. Similar defects of MIBG and FDG uptake have been found in the acute and subacute phases, despite slightly reduced perfusion in TTC.201Tl, 123IBMIPP, 123I-MIBG SPECT showed that the recovery of the decreased uptake mostly occurred in the order of 201Tl, 123I-BMIPP, and 123I-MIBG.et al. have measured regional cerebral blood flow, a well-established index of brain activity using 99mTc ethyl cysteinate dimmer SPECT, and demonstrated a significant cerebral blood flow increase in the hippocampus, brainstem, and basal ganglia paralleled by a decrease in the prefrontal cortex in the acute phase of TTC.29A positron emission tomography using However, there are only a few reports involving nuclear cardiology imaging for the variants of TTCMoreover, these findings are similar to those observed in acute myocardial infarction, where reperfusion therapy was performed, and myocardial salvage was successful. In patients with acute anterior infarction, a threshold of 50% of maximal Tc-99m sestamibi uptake had the best predictive value  for improvement of LV function.This study has several limitations. Firstly, it was an observational, retrospective analysis, and a single-center study with a relatively small number of patients. Secondly, this study evaluated only myocardial blood flow using Tc-99m sestamibi but did not evaluate the abnormalities of myocardial metabolism and sympathetic nervous activity associated with TTC and rTTC. Thirdly, this study evaluated only TTC  and rTTC , with no other variants . Fourthly, in this study, we evaluated patients who were able to undergo scintigraphy in the acute and chronic phases. Patients who could not perform scintigraphy in the acute phase due to poor general conditions were excluded. LVEF was relatively maintained in both the TTC and rTTC groups, which may have affected the results. Fifthly, there were relatively more asymptomatic patients in our study compared to past cohort studies. Finally, there might be a selection bias because we did not include all TTC patients but only those who had undergone scintigraphy in the acute and chronic phases in this study. Future studies with larger patient cohorts are required to overcome these limitations and to validate our findings.This study was nuclear imaging that investigated TTC and rTTC pathophysiology using Tc-99m sestamibi. Our findings revealed that uptake of Tc-99m sestamibi was similarly reduced in the acute phase but improved in the chronic phase in both TTC and rTTC groups.Our findings suggest that reversible disorders, such as microcirculation, myocardial cell membrane, and mitochondria may be involved in the pathophysiology of TTC and rTTC.The findings on myocardial perfusion imaging of TTC and rTTC are similar to those of stunned myocardium found in acute coronary syndrome. Even in the evaluation of uptake of Tc-99m sestamibi, the degree of reduction in the acute phase remains within the range in which the viability can be predicted in acute coronary syndrome. Our findings suggest that reversible disorders such as microcirculation, myocardial cell membrane, and mitochondria may be involved in TTC and rTTC pathophysiology.Supplementary file1 (PPTX 14273 kb)Below is the link to the electronic supplementary material.


The use of glycosylated hemoglobin as a diabetic glycemic control and cardiovascular risk marker is well documented. It has also been suggested as a marker for early diastolic hemodynamic changes leading to clinical heart failure, but is less well characterized. This study explored the association between elevated glycosylated hemoglobin and liver Fibrosis-4 values and worsening measures of diastolic cardiac function in order to assess their potential as early serologic markers in cardiovascular disease prevention.A retrospective cohort analysis was conducted in 102 patients presenting to the Parkview Medical Center health system who had received a full resting echo characterized by normal systolic ejection fraction and clinical risk factors associated with stage A heart failure in conjunction with glycosylated hemoglobin and Fibrosis-4 scores within a 3-month time window. Using regression analysis, measures of diastolic cardiac function were assessed in conjunction with rising glycosylated hemoglobin levels characterized as <6.5 and >6.5 and Fibrosis-4 scores after controlling for the presence of hypertension, coronary artery disease and valvular heart disease. Glycosylated hemoglobin levels >6.5 were significantly associated with a higher E/e’ ratio and closely associated with an elevated left atrial volume index both indicative of elevated left atrial pressure as a sensitive marker for diastolic cardiac dysfunction. Fibrosis-4 scores did not appear to be clinically associated with progression of diastolic dysfunction.Thus, glycosylated hemoglobin may act as an early marker for identifying patients at increased risk for the progression of stage A heart failure. Fibrosis-4 scores do not appear to be related. Additionally, while the association of glyco Hb elevation with an advanced clinical cardiovascular syndrome described as diabetic cardiomyopathy (beyond the classic cardiac risk factors associated with diabetes mellitus) has also been well documented, the use of advanced glycation end products (AGE) as both a marker of, and treatment target for the early diastolic hemodynamic changes of diabetic cardiomyopathy, has been suggested but is less well characterized6–8,14.The classic association of glycemic control, as represented by glycosylated hemoglobin (glyco Hb or glyco%), with progression or improvement of microvascular and macrovascular clinical complications, is well documented9–11. Estimates suggest that Stage A heart failure may comprise greater than 50% of a community’s patient population and patients are commonly seen in primary care, endocrinology, cardiology and other clinics5.People with Stage A heart failure have normal cardiac structure and function but also have predisposing risks for cardiovascular disease which may not yet have manifested as symptoms of heart failure12,13, stage A heart failure patients may be an important target for a new therapeutic mechanism to deploy widely in preventative cardiovascular care. Showing an association between a commonly used metabolic marker and progressive hemodynamic cardiac disease would provide support for initiating medication therapy–classically prescribed in the diabetic context–to earlier use in the cardiac context, with or without a concomitant indication for hypoglycemic therapy.In light of cardio metabolic agents such as SGLT2 inhibitors which show promise in cardiovascular disease primary preventionOur study examined whether glyco Hb could be isolated as a hemodynamic marker of diastolic cardiac dysfunction in diabetics with stage A heart failure, who may or may not yet need initiation or titration of hypoglycemic therapy. Secondarily, a non-invasive easily obtainable marker for liver fibrosis  was also assessed for its correlation to diastolic function and potential utility as a treatment marker.β > 0.8) for detection of a 5% change in left atrial volume (LAV) examining the registry from most- to less-recent index encounter to a p value of less than 0.05 until the N value was met.A community-based population cohort registry of all patients was identified by retrospective chart review of patients who had presented to Parkview Medical Center’s in-patient and outpatient services in Pueblo County Colorado from January 2019 to June 2020 and who had obtained a full resting echocardiogram characterized by normal LV systolic function in conjunction with glyco Hb, brain natriuretic peptide (BNP), CBC and CMP within a concomitant 3-month time frame. 2263 patients were identified. A sample of 102 participants was randomly selected for this study. All the study participants’ procedures and related parameters were part of a previously ordered medically indicated clinical evaluation. The selected sample size was determined by power analysis , body mass index (BMI), body surface area (BSA), brain natriuretic peptide (BNP), previous history of hypertension (HTN), cardiac valvular disease and coronary artery disease (CAD) were also recorded. All data was compiled from retrospective medical records for the participants selected for the sample. This study was sanctioned and approved by the Parkview Medical Center Institutional Review Board.16. The presence of hypertension was defined as greater than 140/90 measured closest in time to the index echocardiogram. Valvular disease was defined as any regurgitation or stenosis noted to be greater than mild. Coronary artery disease was defined as any of the following: any regional wall motion abnormality on echo and/or cardiac catheterization showing at least one vessel with 50% or more stenosis. All labs were processed through Parkview’s central laboratory.Transthoracic echocardiography was performed in accordance with published standards and interpreted by a board-certified cardiologist independent of any knowledge of this studyMeans, standard deviation and range were calculated for continuous variables while frequencies and proportional percentages were calculated for categorical variables. All descriptive statistics were calculated using PROC MEANS and PROC FREQ from SAS/STAT v.9.4 . Generalized additive models (GAMs) were used to evaluate the association of the dependent variables glycemic percentage (Glyco Hb) and liver fibrosis (FIB-4) to the independent variables of HTN, valvular disease, CAD, age, BMI, BNP, LAVI and E/e’.17 and thus, BMI was the only one included; secondly, E, Lateral e’ and E/e’ are functionally related to each other and thus only E/e’ was included in the model; lastly, LAVI and LADI. Only LAVI was included in the model since it is the strongest method to predict any and moderate to severe diastolic dysfunction.18Effects were introduced into a semiparametric model by including the effects of gender, HTN, valve disease and CAD as parametric independent variables  and age, BMI, BNP, LAVI and E/e’ as smoothing splines with 3 degrees of freedom (continuous variables). Models were fitted independently by dependent variable (Glyco Hb and FIB-4) and assumed a Gaussian distribution for the residuals. Some variables were removed from the final model to avoid multi-collinearity: firstly, BMI and BSA which are intimately correlatedP-values <0.05 were considered statistically significant.All modeling was performed using PROC GAM in SAS/STAT v.9.4. Modeling effects are displayed as risk ratios with their 95% confidence intervals. Non-linear associations of continuous variables evaluated as smoothing splines are evaluated through an analysis of deviance using a cubic pattern (3 degrees of freedom). Smoothing component plots included a 95% curve-wise Bayesian confidence band for each component. Two-tailed In total, 102 patients were retrospectively identified who met inclusion and exclusion criteria. Their descriptive characteristics including mean, standard deviation, and range of values are shown in p < 0.05) between glyco Hb with BMI (P = 0.0043) and E/e’ (P = 0.0345). For both models, glyco Hb and FIB-4, neither sex nor comorbidity confounders of CAD, valve disease, and HTN were significantly associated  in the FIB-4 model. Although it remained non-significant for FIB-4 prediction (P = 0.2043).Parameter estimates obtained through GAMs displayed as risk ratio significant association , detected only an increased risk associated to age for the low group when estimating glyco Hb. This data is presented in For low group vs high group models, only age was detected as significantly predictive. No predictive potential was detected in general for FIB-4 criteria in the main model and in the subsequent low group vs high group model iteration.19 These processes, at least in part, are thought to play a role in the development of cardiac fibrosis independent of the classic vascular complications related to diabetes mellitus.Advanced glycation end product (AGE) formation is characterized by the glycation of plasma proteins during longstanding hyperglycemia. These AGE’s then stimulate transmembrane receptors of advance glycation end products (rAGE) on somatic cells including cardiac myocytes resulting in alteration of intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals.20In contrast to transmembrane rAGE, soluble receptors for advance glycation end products (sRAGE) function to reduce risk associated with transmembrane rAGE by the pre-transmembrane binding of AGEs and subsequent reduction of intracellular rAGE signaling. Specific sRAGEs have been identified and may have the potential to serve as markers for AGE-related cardiac risk.21, which is what prompted the evaluation of FIB-4 in this study.As an early glycation end product, glyco Hb is nicely positioned as a hemodynamic risk marker inside this mechanism. Additionally, as lipids are thought to play a role in hepatic steatosis and liver fibrosis as well as in cross linking to form more advanced glycation end products capable of stimulating transmembrane rAGE, easily obtainable markers for liver fibrosis could serve as markers for cardiac fibrosis22. The difficulty was in using diastolic dysfunction as an independent variable which could be seen as excluding our cohort from true stage A characteristics.Stage A heart failure patients are an attractive cohort to study, in that early intervention may provide significant attenuation of disease in this patient population. The definition of stage A heart failure in this study was applied to a cohort primarily defined by normal LV systolic function. In controlling for patients with underlying hypertension, CAD, and valvular heart disease we further isolated the cohort to a stage A definitionGiven that the degree of diastolic dysfunction based on E/A changes needed to advance patients from the stage A category is not clear in the definition of stage A heart failure, we tried to utilize the more sensitive “pre-clinical” markers for left atrial pressure and chronic diastolic dysfunction: LAVI and E/e’.The use of the dependent variables glyco Hb and FIB-4 was designed to capture simple and easily obtainable markers for cardiac fibrosis. In that current diabetes guidelines recommend a goal for hypoglycemic therapy to a glyco Hb of less than 7.5, defining the study group as those who meet a definition for DM but may not yet require hypoglycemic therapy makes the results more applicable for cardiac risk reduction, as opposed to simple glycemic control.25FIB-4, used as a marker for liver fibrosis which is often associated with hyperglycemia and hyperlipidemia and of the same potential mechanism as metabolic cardiac fibrosis was attractive in that age as detected in our low group model iteration, platelets, AST and ALT are its formulaic components, however we did not find an association between FIB-4 and measures of diastolic dysfunction. Additionally, the lack of a clear correlation between cardiac fibrosis markers and BNP is notable given that there is evidence that higher levels of BNP are related to progressive diastolic cardiac dysfunction. This lack of correlation may be explained and/or mitigated by the study design involving only stage A  and not progressive stages of heart failure.23. Left atrial volume was seen as reflective of “the cumulative chronic effect of LV filling pressure over time”. The E/e’ ratio was also used as a doppler measure of diastolic function because it combines the ratio of a transmitral flow measurement  with a tissue Doppler measurement (a marker of LV diastolic pressure) which is more sensitive for diastolic dysfunction.24Two measures of diastolic function were used to assess the AGE-myocardial hypertrophy hypothesis6. This distinction is what sets diabetic cardiomyopathy apart from standard diabetic vascular risk factors and raises the specter of earlier hemodynamic primary preventative cardiac therapy even earlier than standard glycemic goals may dictate, especially in light of SGLT2 inhibitor effects.Distinguishing glyco Hb as a compliance marker for progressive cardiac diastolic dysfunction beyond a non-specific vascular risk marker has been demonstratedIn patients with clinical cardiovascular risk characterized as stage A heart failure, glyco Hb may be useful as a sensitive marker to identify those most at risk for disease progression based on diastolic hemodynamic parameters. Additionally, glyco Hb may identify target patients for whom a preventative cardiovascular treatment regimen, via the cardioprotective effects of newer glycemic agents, may be beneficial even prior to a glycemic indication for therapy.


As the population ages and the prevalence of heart failure increases, cardiologists and geriatricians can expect to see more elderly patients with heart failure in their everyday practice. With the advancement of medical care and technology, the options for heart failure management have expanded, though current guidelines are based on studies of younger populations, and the evidence in older populations is not as robust. Pharmacologic therapy remains the cornerstone of heart failure management and has improved long-term mortality. Prevention of sudden cardiac death with implantable devices is being more readily utilized in older patients. Advanced therapies have provided more options for end-stage heart failure, though its use is still limited in older patients. In this review, we discuss the current guidelines for medical management of heart failure in older adults, as well as the expanding literature on advanced therapies, such as heart transplantation in older patients with end-stage heart failure. We also discuss the importance of a multidisciplinary care approach including consideration of non-medical co-morbidities such as frailty and cognitive decline. With the advancement of medicine, technology, and preventative care, the average life expectancy at birth has increased and is expected to continue rising. Worldwide, there has been an increase in the population 65 years and older ,2,3,4 asThe prevalence of heart failure increases significantly with age and is estimated to affect more than 6 million adults in the US . PrevaleLong-term heart failure mortality has improved with guideline-directed pharmacologic therapy and treatment of risk factors, though absolute mortality remains approximately 50% within five years of diagnosis . CurrentPatients greater than 75 years old are under-represented in pivotal trials supporting the use of guideline-directed medical therapies. These trials also excluded those who did not meet criteria for creatinine clearance, heart rate, and systolic blood pressure. For example, the US Carvedilol Heart Failure study excluded patients with a systolic blood pressure greater than 160 mmHg and heart rate less than 68 beats per minute, and the average age of participants was 58 years old . The SOLIn addition to pharmacologic therapy, primary prevention of sudden cardiac death is a routine part of guideline-directed therapy in select patients with cardiomyopathy and heart failure. Implantable cardioverter-defibrillator (ICD) therapy is recommended for patients with a left ventricular ejection fraction of 35% or less and New York Heart Association (NYHA) class II or III symptoms. Cardiac resynchronization therapy (CRT) is recommended for patients with a left ventricular ejection fraction of 35% or less and left bundle-branch block with a QRS duration of greater than 150 milliseconds, in addition to NYHA class II–IV symptoms . NotablyAlthough the mortality benefits of these devices have been shown in landmark trials ,19,20,21It is important to note that recommendations for device therapy are for patients with an expected meaningful survival of greater than one year, though decision making can be challenging given concurrent comorbidities, geriatric conditions, and how “meaningful survival” is defined. Additionally, procedural complications and routine maintenance and monitoring of implanted devices must be considered. As such, it is important to assess patients on an individualized basis when deciding who would be an appropriate candidate to refer for defibrillator or cardiac resynchronization therapies. Decision aids for ICDs are available and can be helpful in facilitating these conversations . It woulDespite evidence-based medical and device-based therapies, about 10 percent of heart failure patients progress to “advanced” or end-stage heart failure. Advanced heart failure is characterized by progressive symptoms including exercise intolerance, weight loss, refractory volume overload, and hypotension . When hePositive inotropic drugs such as dobutamine and milrinone improve hemodynamics in decompensated heart failure with low cardiac output and evidence of poor end-organ perfusion. They are commonly used short-term in patients with cardiogenic shock to maintain systemic perfusion while the acute precipitating event is treated or to bridge patients to a more durable advanced therapy. Due to concerns regarding increased mortality associated with their use, long-term inotropes are not routinely recommended. However, for select patients who cannot be weaned from inotropes or who receive significant symptomatic benefit from their use, long-term inotropes can be considered. Accordingly, current heart failure guidelines provide a Class IIb recommendation for long-term ambulatory use of inotropes as a palliative option for patients with end-stage heart failure who are not candidates for advanced therapies . While cImprovement in mechanical circulatory support technology has led to an increase in left ventricular assist device (LVAD) implantations, decreased in-hospital mortality, and improved survival ,38. The Existing data regarding outcomes in older adults with LVADs remain limited and contradictory. Analyses of INTERMACS database and National Inpatient Sample of older adults concluded that age remains a predictor of poor outcomes after LVAD implantation ,42. PatiPotential complications such as bleeding, which older patients are more likely to suffer from ,43, infeCardiac transplantation remains the best therapeutic option for patients with end-stage heart failure. In the early era of heart transplantation, older patients were not considered transplant candidates, and further screening was recommended for patients over the age of 50 years old . Due to When caring for older patients with heart failure, a multifactorial approach should be taken that includes assessment and management of associated geriatric syndromes such as cognitive impairment, frailty, and malnutrition, which can play a role in hospitalization, quality of life, morbidity, and mortality.Polypharmacy, defined as five or more medications, is nearly universal in heart failure patients due to multimorbidity and guideline-based medication recommendations. Heart failure patients take an average of 10 medications, all of which carry risk for drug interactions and adverse reactions . There iRecognizing the need to re-examine the benefits and risks of medication use, especially in older adults prone to adverse events, the process known as deprescribing is gaining momentum worldwide. Deprescribing focuses on removing or reducing unnecessary or potentially harmful medication use with the goal of improving outcomes, taking into account an individual’s overall physiologic status, stage of life, and goals of care . OngoingFor providers and patients interested in pursuing deprescribing, Krishnaswami et al. provide a five-step approach to deprescribing that includes: (1) reviewing and reconciling medications, (2) assessing the risk of adverse drug events, (3) assessing candidacy of individual medications, (4) prioritizing drug discontinuation, and (5) discontinuing medications and implementing monitoring protocols . The decThe prevalence of cognitive impairment is approximately 16 to 20 percent of the general population and 40 percent amongst patients with heart failure , with anFrailty is a syndrome that is characterized by the exaggerated decline in function and increased physiological vulnerability to stressors , commonlFrailty assessment is instrumental in helping to guide treatment plans that will maximize patients’ likelihood of a positive outcome and should be implemented as part of routine heart failure management in older adults. The Fried phenotype method  is a widAs the population ages and medical therapy improves, the number of older heart failure patients is expected to increase as well. Although medical therapy has improved outcomes in heart failure, mortality and hospitalization remain high. Older patients were historically underrepresented or excluded from the landmark trials that led to the current heart failure guidelines, though we continue to apply the current recommendations to our older patients.Heart transplantation remains the best therapeutic option for end-stage heart failure, though age remains a barrier to transplant at many institutions. Alternatively, technological advances have allowed more patients to receive LVAD in end-stage heart failure, but older patients are more prone to complications. Newer LVAD technology may mitigate those complications, but the number of older LVAD patients has not increased in recent years. In our older patients with heart failure, it is also important to take a multifactorial approach to care, while considering geriatric syndromes, polypharmacy, and expected survival when prescribing and offering advanced therapies.


Accelerated idioventricular rhythm (AIVR) is a wide QRS complex dysrhythmia that, as far as pediatric population is concerned, occurs mostly in children with underlying systemic or heart disease. Its clinical course is thought to be typically benign in otherwise healthy children and treatment to be completely needless. Existing guidelines/recommendations are based entirely on cases that had low daily burden of AIVR, and those referring to treatment itself are very unspecific. Pharmacologic therapy has been mostly unsuccessful and catheter ablation as a way of treatment has been only sporadically reported. This article is a case report with a literature review that aims to practically separate the age groups into newborn and older children and to emphasize the different clinical outcomes of children with occasional and frequent AIVR. There are only a few cases so far describing undesirable outcomes of this condition, and most of these patients had high daily burden of AIVR. To be more specific, among 38 healthy children older than 1 year reported in total, 6 had undesirable outcomes, short-term in terms of developing malignant arrhythmia or long-term in terms of developing cardiomyopathy/heart failure.An 11-year-old boy had been referred to our center for a workup of incidentally discovered wide-complex arrhythmia. He was asymptomatic, with no underlying cardiac or systemic diseases. Continuous heart rate monitoring detected AIVR during most time of monitoring. In 24-h Holter-ECG, wide QRS complexes accounted for 73%. With parental consent, we conducted an electrophysiological study accompanied by radiofrequent ablation of ectopic focus, which lead to an instantaneous sinus rhythm that continued during the entire follow-up.AIVR is a rare dysrhythmia in the pediatric population, typically considered benign. Nevertheless, more than a few cases evidence its harmful potential, short-term in terms of developing malignant arrhythmia or long-term in terms of developing cardiomyopathy. Gathering more knowledge and experience along with conducting further studies is essential for the enhancement of understanding this condition, and selecting potentially vulnerable patients as well as their treatment. Accelerated idioventricular rhythm (AIVR) is a wide QRS complex arrhythmia that is consisted of at least three consecutive ventricular complexes which are mostly monomorphic . It is cIn the pediatric population, it is usually noted in patients with congenital cardiac defects and is relatively rare without underlying cardiac diseases. Mostly being asymptomatic, it is often an incidental finding on routine electrocardiograms (ECG) . MajoritNevertheless, the performed literature review pointed out the need to separate children in groups according to age into newborns and older children and according to the daily proportion of AIVR into sporadic and frequent, due to differences in clinical sequence of the disease and the prognosis of the diagnosis.Recommendations for treatment of this dysrhythmia in children are modest. In 2014, a consensus statement was issued suggesting that if the patient is asymptomatic, has no hemodynamic repercussion, no arrhythmogenic myocardial disease, or existing myocardial dysfunction, there are no indications for active treatment. Literature supporting these recommendations do not mention patients with frequent AIVR . HoweverAn 11-year-old male had been referred to our center from another hospital for a wider workup of incidentally discovered wide-complex arrhythmia. He had never experienced any possible cardiac etiology symptoms such as palpitations, chest pain, dizziness, or syncope. Other than mild tachycardia, his cardiovascular examination as well as the remainder of his physical examination was normal.After preforming a 12-lead surface electrocardiogram (ECG), he was placed on a continuous heart rate monitor in-hospital (telemetry) during 4 days where we evidenced accelerated idioventricular rhythm almost constantly during the monitoring, except when in exertion. The QRS morphology of sinus rhythm was normal , whereas that of AIVR was right bundle branch block (RBBB) type and superior axis . , with maximum, minimum, and average heart rates of 150 beats per minute (bpm), 49 bpm, and 88 bpm, respectively. During the AIVR, the heart rate was approximately 105 bpm.The exercise treadmill test revealed converting the idioventricular rhythm to sinus rhythm at a threshold heart frequency of about 120 bpm and higher, as well as returning to the idioventricular rhythm as the frequency got lower during the rest period. . We used the CARTO 3D electroanatomic mapping system (Johnson&Johnson) and placed catheters in the coronary sinus, right ventricle, and the His position. The EP study confirmed the mechanism of tachycardia by entrainment from the right atrium and right ventricle. Afterward, through the femoral artery, the Pentaray catheter was placed in the left ventricle and activation mapping was conducted. His, left branch, anterior and posterior fascicle were marked Fig. C.Fig. 2Cmax), and average frequency (Favg) verified by 24-h Holter-ECGs during evaluation and after the procedure performed in September 2020.Moreover, during 17 months after the ablation, we conducted a few 24-h Holter-ECG and treadmill tests, all had normal values for the patients age. Table AIVR is a wide QRS complex arrhythmia consisting of at least three consecutive, monomorphic ventricular complexes . In chilGiven the extremely high proportion of wide QRS complexes in form of AIVR in 24-h Holter-ECG as well as on continuous heart monitoring during hospitalization, in this case, we opted for treatment even though the patient was asymptomatic and still did not have evidence of left ventricular dysfunction. We aimed to terminally end this condition and improve patient's future quality of life. Long-term use of antiarrhythmics can potentially have an arrhythmogenic effect, and in AIVR, the success of drug therapy is questionable , 7. Due A systematic literature search was conducted to identify pediatric patients with AIVR. Please note, that patients with significant systemic illness or with underlying structural or functional heart disease were excluded. MEDLINE /PubMed and Scopus databases were searched (from November 2021 to June 2022).In total, 82 adequate patients were identified, of whom 44 were newborns and 38 were postneonatal age. These two groups need to be separated in the literature review as well as in clinical treatment due to different clinical courses, outcomes, and prognoses of this dysrhythmia.With some regularity, AIVR can be seen in otherwise healthy newborns during workup for clinically revealed arrhythmia or is an accidental finding. All described neonatal cases were hemodynamically stable and asymptomatic during arrhythmia, which was transient and self-limiting in otherwise healthy children Table . AttemptIn the postneonatal group, 38 children who did not have associated congenital heart disease or other chronic diseases were reported altogether. A larger group of patients was first described by MacLellan-Tobert in her 1995 paper. 12 pediatric patients were described, 2 of whom were newborns and 4 had CHD. The ECG spontaneously normalized in 8. Not one was reported to have symptoms or signs of hemodynamic instability. They were followed up for an average of 68 months [The first review of the literature of the last century was published by Reynolds and Pickoff in 2001 , which iIn a vast number of articles published before the 2000s there is no exact data on the duration of arrhythmia, the total daily share of an abnormal rhythm, frequency variability, left ventricular ejection fraction (LVEF), etc., 23, whiTable Wang and co-workers published a paper on ventricular arrhythmias in children in 2010, 77 of them from 1980 to 2010. 19 had AIVR, of whom 6 were newborns. All children were hemodynamically stable, less than half showed symptoms, the most common being palpitations. All underwent 24-h Holter-ECG, and no data on daily burden was available. Cardiac function estimates were normal except slight reduction in ejection fraction in two patients, both spontaneously regressed. 6 were pharmacologically treated which was followed by arrhythmia resolution, but, according to the authors, it is impossible to say whether it was the effect of the drug itself or spontaneous resolution, which occurred in 13 who were not treated. No EPS has been performed [Chen et al. enrolled 8 patients in their study, of whom 2 were boys aged 16 and 17. The 16-year-old was asymptomatic, with a dominant AIVR burden of 99.6%, and LVEF of 45%. 17-year-old had intermittent AIVR, with a daily burden slightly higher than 20%. AAD therapy was tried in both. Complete arrhythmia suppression did not occur. Both underwent an EPS with RF ablation that successfully restored sinus rhythm .In 2017, Errahmouni et al. reported a 12-year-old with previously diagnosed AIVR who acutely presented with heart failure LVEF 25%) and cardiogenic shock. He was admitted to the intensive care unit (ICU) and treated with mechanical ventilation, electrocardioversion, inotropic drugs, and amiodarone to which the arrhythmia was terminated. Amiodarone therapy was continued after discharge, but when the therapy withdrawal was attempted, the boy was rehospitalized under the same symptoms and treated as before. RF catheter ablation was successfully performed in a steady-state. After 4 weeks, complete recovery of LVEF, with sinus rhythm and RBB in ECG was marked [% and carErgul et al. reported a case of left coronary cusp cryoablation originating AIVR in an 11-year-old who was previously followed up due to asymptomatic AIVR. He had experienced an aborted cardiac arrest during sleep and had been resuscitated for 5 min. 24-h Holter-ECG revealed incessant AIVR, consisting of up to 90% of the whole record, and two torsades de pointes attacks, triggered by the AIVR-induced “R on T” phenomenon, resulting in syncope and cardiac arrest. Transthoracic echocardiography revealed no structural cardiac defect but mild left ventricular systolic dysfunction. The cryoablation was performed in a steady state. 9 months later, he was asymptomatic, without any PVCs or AIVR, with normal cardiac function .The latest reported case is from 2021 by Kappy et al. It is more similar to the cases described earlier, about an accidental finding of intermittent AIVR in a 13-year-old during post-tonsillectomy bleeding workup. As she stayed asymptomatic and had no cardiac dysfunction, she was discharged without therapy, with a follow-up recommendation in 18 months .As of last, we would like to point out one rare case report of long-term, high-burden AIVR with a consequent decrease in LVEF described by Mine in 2012. A 35-year-old woman had been diagnosed with AIVR for 12 years. It was detected accidentally, the rhythm was persistent with an average sinus-like frequency. At the age of 32, she developed palpitations and shortness of breath on exertion, beta-blocker therapy was introduced, which was ineffective. After three years of therapy, her regular workup showed reduced LVEF, therefore it was decided to perform RFA. After ablation, rhythm was restored to sinus and cardiac function recovered . This isEvidently, in case there is no need for acute treatment due to hemodynamic instability or reduced myocardial function, it is necessary to evaluate the share of wide QRS complexes, in other words, premature ventricular complexes (PVC). This is important since the daily burden of PVCs is the most prominent predictor of cardiomyopathy . One of In AIVR, when the frequency is high, heart contractions are mostly in a dyssynchronous manner so we can expect cardiomyopathy somewise comparable to frequent PVCs. Yet there is not enough data on which percentage of PVCs in which period causes impairment in left ventricle function in the case of AIVR. According to Merchant et al., pathophysiologically, cardiomyopathy arises due to impaired, dyssinchron mechanichal myocardium contraction and relaxation, intraventricular as well as interventricular. It occurs in pacemaker-induced cardiomyopathy (PICM), left bundle branch block cardiomyopathy, as well as in premature ventricular contraction-induced cardiomyopathy, which can pathophysiologically be conceptualized as variants of broader dyssynchrony-associated cardiomyopathy. Not only the share but also the width of QRS complexes contributes to dyssynchrony, proportionally .In 2021, Wang et al. published a study they conducted from 2002 to 2018, including 27 patients, in which it was shown that AIVR burden larger than 73.8% could predict impaired left ventricular ejection fraction with 100% sensitivity and 94.1% specificity. Their conclusions go even further, claiming that, unlike transient AIVR, which requires no treatment, frequent AIVR requires optimal treatment, and catheter ablation to be the utter resort in some patients. Also, they find AIVR burden over 70%, impaired LVEF, or syncope/presyncope to be indications for catheter ablation [The clinical course of AIVR seems to be of low significance in the pediatric population. However, our case added up to not many cases found in the existing literature. The course of this dysrhythmia significantly depends on daily burden of AIVR, which if high, might not be as benign as thought, in meanings of short-term or long-term outcomes.Unfortunately, with such a low number of similar patients so far, cut-off values or therapeutic direction hadn't been determined, at least not evidence-based. Radiofrequent ablation as a modality of treatment of high burden AIVR in hemodynamically stable patients with normal myocardial function to prevent possible cardiomyopathy is not common.We believe that reporting various clinical presentations and modalities of therapeutics in AIVR patients is important to achieve improvement of diagnosing, treatment guidelines, and overall understanding of this dysrhythmia.


After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established. Methods and Results: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models . A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively. Conclusions: Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity.Background: Decreased peak oxygen consumption during exercise (peak V While it is plausible that decreased peak Vo2 in HFrEF reflects, at least in part, inadequate tissue oxygen delivery during exercise due to a reduced cardiac output [o2 and hemodynamic dysfunction has long been observed [Diminished exercise capacity is a cardinal feature of advanced heart failure, and a strong association between decreased peak oxygen consumption  quantify the association between post-transplant peak Vo2 and mortality and (2) identify potential pathophysiologic processes that may explain this association.Because multiple comorbidities factor into the peak VThe first and last authors (T.C.H. and E.Y.B.) had full access to all the data in the study and take responsibility for its integrity and the data analysis. Requests to access deidentified data from qualified researchers trained in human subject confidentiality protocols should be sent to the corresponding author. Unidentified Stata code for this analysis is available upon request.o2. Baseline pre- and post-transplant clinical data were recorded from the electronic medical record, including demographics, pre- and post-transplant comorbidities up to the time of CPET, laboratory values at the time of CPET, post-transplant echocardiographic data up to one year post-CPET, the incidence of acute cellular rejection grade 2R or 3R or antibody mediated rejection prior to CPET, and the CPET results themselves. This study was approved by the University of Pennsylvania Institutional Review Board with a waiver of informed consent.We performed a retrospective analysis of all adult heart transplant recipients who were transplanted from March 2000 to November 2011 at the Hospital of the University of Pennsylvania, excluding multiorgan recipients and patients undergoing cardiac re-transplantation. Survival status was observed through October 2019 using data merged from the Penn Transplant Institute. This era was selected due to a clinical protocol at the time in which all patients underwent a post-transplant cardiopulmonary exercise test (CPET) within one year of transplant if clinically able. Patients who underwent CPET outside of their first post-transplant year were excluded, as were four patients with missing peak Vo2 and carbon dioxide production (Vco2) at peak exercise. Studies were interpreted by an advanced heart failure cardiologist.Data from CPET were acquired retrospectively from the electronic medical record. All patients performed one symptom-limited CPET within the first post-transplant year according to our standard clinical practice, using a treadmill with a low- or moderate-intensity ramped protocol until exhaustion, the onset of limiting symptoms, or the development of a contraindication to continued exercise. Breath-by-breath expired gas analysis was used to obtain continuous estimates of Vo2 was determined as the highest 10-s averaged samples obtained during exercise. We estimated the % of predicted peak Vo2 using the Fitness Registry and the Importance of Exercise National Database (FRIEND) equation based on age, sex, and weight [o2 is conventionally standardizing for total body mass; however, because Vo2 is influenced primarily by muscle mass and can be reduced out of proportion to heart failure severity in obese subjects [o2 indexed separately for total body mass in kilograms  and estimated lean body mass . Lean body mass was estimated from weight, height, age, and ethnicity using a formula validated against dual-energy X-ray absorptiometry  in a sample of 14,000 US adults [2 pulse was calculated as the ratio of absolute peak Vo2 to peak heart rate.Absolute peak Vd weight . Peak VoS adults . Heart rco2 to Vo2 at the time of exhaustion. Maximal Volitional exercise was determined using a peak RER ≥ 1.0, based on guideline recommendation and application in recent large studies of exercise in HFrEF [o2 to the left ventricular ejection fraction.The respiratory exchange ratio (RER) was determined from the ratio of Vin HFrEF ,13,14,15o2 values above and below the sample median using the two-sample t-test for continuous variables  and the Chi-squared test or Fisher’s exact test as appropriate for categorical variables. All time-to-event analyses considered the time to death or re-transplantation from the time of transplant, referred to hereafter as simply “mortality” given the low incidence of re-transplantation. Differences in mortality over time in relation to absolute peak Vo2, %Vo2, peak Vo2, body mass, peak Vo2, lean and O2 pulse were assessed in univariate and multivariable models as described below.Continuous data are expressed as mean ± standard deviation (SD), while categorical data are expressed as frequency and proportions. We compared baseline characteristics between patients who had peak Vo2 parameter to quantify its crude and adjusted association with mortality. Model 1 was unadjusted. Model 2 was adjusted for demographics including age, race/ethnicity, sex, and the number of days from transplant to CPET. Finally, model 3 was adjusted for model 2 variables plus pre-transplant pulmonary vascular resistance (PVR), type 2 diabetes, ischemic cardiomyopathy, peripheral vascular disease, chronic obstructive pulmonary disease and post-transplant hemoglobin (measured at the time of CPET) [Three Cox proportional hazard models were constructed for each Vof CPET) . All indof CPET) . A two-so2 using flexible parametric survival models [o2 cutoffs for predicted survival below 80% are presented at 5, 10, and 15 years post-transplant. One-year survival was also modeled, but a cutoff for 80% survival at 1-year did not exist within the measured range of %Vo2. All analyses were performed in Stata version 16 .Next, we modeled survival at 1, 5, 10 and 15 years post-transplant as a function of post-transplant %Vl models . The %Voo2 measurements on 235 patients. Reasons for missing peak Vo2 measurements were: 4 died prior to one year without undergoing CPET, 38 performed CPET after the 1-year cutoff, 4 performed CPET but were missing peak Vo2, 67 were unable to perform CPET due to prolonged index hospitalizations or severe deconditioning, and 19 performed CPET with submaximal exercise. The RER for the patients excluded for submaximal exercise ranged from 0.8 to 1.0, while the RER for patients performing maximal exercise ranged from 1.0 to 1.44.A total of 367 patients underwent single-organ, first-time heart transplantation at the University of Pennsylvania during the study period . Of theso2, %Vo2, and Vo2 indexed to body mass or lean mass. The median %Vo2 was 49% (IQR 42 to 60%).During follow-up of the 235 patients in the cohort, there were 93 deaths (40%) and 4 retransplants (1.7%). The range of follow-up was 115 days to 18.9 years . o2 below median (p < 0.001), male sex , lower peak heart rate , lower weight , and lower BMI . Some of these relationships may seem paradoxical , but this is because younger patients tended to have lower peak Vo2 relative to their age-predicted values than older patients, in spite of having greater absolute peak Vo2 measurements. O2 pulse, the ratio of absolute Vo2 to peak heart rate, was also lower in individuals with %Vo2 below median , suggesting impairments in the arteriovenous O2 content or stroke volume at peak exercise. Distributions of pre-transplant comorbidities and ethnicity were similar. No differences in post-transplant LVEF were observed between the groups , and there was no association between acute cellular rejection and %Vo2 . No patients who performed maximal exercise CPET had experienced antibody mediated rejection prior to CPET.Several baseline parameters were associated with a %Vw median . This ino2 were significantly associated with mortality in unadjusted and multivariable adjusted models, with a large effect size  was associated with a 34% decrease in mortality , equivalent to a 2.4% decrease in mortality per each %Vo2. After adjusting for demographics, comorbidities, and the time from transplant to CPET —each SD increase in %Vo2 was associated with a 32% decrease in mortality , equating to a 2.3% decrease in mortality per %Vo2. We analyzed the association between peak Vo2 and mortality using alternative weight indices, including unindexed estimates (absolute peak Vo2) and peak Vo2 indexed to total body mass  or estimated lean mass . All of these had estimates comparable to that of the %Vo2  was associated with a 19% decrease in the hazard of mortality . After multivariable adjustment, the HR for O2 pulse was 0.66 . o2 of 49%.All metrics of post-transplant peak Vect size . Estimatthe %Vo2 . Lastly, indices . In unado2  was predicted by a %Vo2 below 29%. At 10 years, the 80% survival threshold (95% CI 74 to 87%) was predicted by a %Vo2 below 64%. Finally, at 15 years, 80% survival (95% CI 69 to 94%) was predicted by a %Vo2 below 88%. Only 5 patients in our sample died within the first year (2%), so no cutoff predicting 1-year survival less than 80% could be estimated.We derived four models predicting survival at 1, 5, 10 and 15 years post-transplant as a function of post-transplant %Vo2 . From eao2 and mortality in ambulatory heart failure was first established over two decades ago [o2 in the early post-transplant period is associated with long-term post-transplant mortality. Our major findings were that: (1) diminished post-transplant peak Vo2 was strongly associated with mortality over nearly two decades of follow-up and (2) this association was independent of parameters known to directly influence Vo2, such as hemoglobin, sex, heart rate, body mass, and the number of days from transplant to CPET.An association between pre-transplant peak Vades ago , and numades ago ,20. In to2 is multifactorial, inVOlving cardiac and extracardiac parameters. Only some of these will respond directly to improved cardiac function, while some deficits are likely to remain, explaining why several studies have shown little improvement in peak Vo2 after heart transplant or mechanical circulatory support [o2 and mortality post-transplant was inherent to peak Vo2 or instead confounded by several common comorbidities. In the fully adjusted model, each SD (14%) increase in %Vo2 remained associated with a 32% decrease in the hazard of mortality . This effect size is in accordance with another single-center study out of Norway that analyzed transplants from the decade prior [The etiology of diminished peak V support ,8. In oude prior , confirmo2 and mortality. Instead, their adjustment had negligible effect. Similarly, the association between Vo2 and mortality was independent of post-transplant factors that can significantly impact the peak Vo2 or mortality, including body mass, LVEF, hemoglobin, creatinine, a history of acute cellular or antibody mediated rejection, the number of days from transplant to CPET, and immunosuppressive regimen. Additionally, the O2 pulse—which indexes the peak Vo2 to peak heart rate—was strongly associated with mortality in all multivariable models. This confirms that the association was not conditional on heart rate response, which can be diminished post-transplant secondary to sympathetic denervation. Based on the strong association between peak Vo2 and survival, higher %Vo2 predicted a greater probability of survival each year post-transplant. Using 80% survival probability as a target, this threshold was predicted at 5, 10 and 15 years by increasing %Vo2 cutoffs of 29%, 64%, and 88%, respectively. If externally validated, this metric could provide a useful prognostic screening tool for the early post-transplant period.These latter comorbidities, though not severe enough to preclude transplant in the first place, could still significantly confound the relationship between Vo2 that is unrelated to cardiac dysfunction or major comorbidities may indicate impaired skeletal muscle function, consistent with the “muscle hypothesis” in chronic heart failure [2 diffusion or deficiencies in mitochondrial density and efficiency [o2 predicts lower post-transplant peak Vo2 [2 pulse, which in addition to correlating with stroke volume also provides an indirect measure of the arteriovenous oxygen difference [Diminished peak V failure . Even in failure ; even mo failure . In chroficiency , and thepeak Vo2 , althougpeak Vo2 . Furtherfference .o2 were determined via a 10 s average rather than 30 s, which may overestimate peak Vo2 . As a single center study with a predominantly white population, generalizability to other sites may be reduced. In this study, most patients did not have pre-transplant CPET to analyze the prognostic importance of the change in parameters from pre- to post-transplant—this is a topic of future interest. Selection bias likely exists in the ability to perform a CPET, per se, thus estimates of association with mortality in the CPET population likely underestimate mortality in the overall heart transplant population that includes patients who were unable to perform CPET. Some covariate data were missing in this study, but no variables had greater than 15% missingness, and we were able to minimize bias through multiple imputation of missing datapoints.This study is retrospective in nature, which increases the possibility for misclassification bias using variables measured for clinical intent. In particular, peak Vo2 during maximal exercise is strongly associated with long-term post-transplant survival. The independent association between peak Vo2 metrics and mortality was independent of several important confounders and factors that contribute directly to Vo2. We observed an association between O2 pulse and mortality, suggesting that diminished post-transplant skeletal muscle oxidative capacity is a link between decreased peak Vo2 and survival. High-intensity exercise conditioning after transplant can safely augment peak Vo2 [o2 would lead to improved survival. If so, more aggressive cardiopulmonary rehabilitation post-transplant would be warranted, with peak Vo2 as an objective target.Post-transplant peak Vpeak Vo2 , but fut