Ventilatory failure, due to the progressive wasting of respiratory muscles, is the main cause of death in patients with Duchenne muscular dystrophy (DMD). Reliable measures of lung function and respiratory muscle action are important to monitor disease progression, to identify early signs of ventilatory insufficiency and to plan individual respiratory management. Moreover, the current development of novel gene-modifying and pharmacological therapies highlighted the urgent need of respiratory outcomes to quantify the effects of these therapies. Pulmonary function tests represent the standard of care for lung function evaluation in DMD, but provide a global evaluation of respiratory involvement, which results from the interaction between different respiratory muscles. Currently, research studies have focused on finding novel outcome measures able to describe the behavior of individual respiratory muscles. This review overviews the measures currently identified in clinical research to follow the progressive respiratory decline in patients with DMD, from a global assessment to an individual structure–function muscle characterization. We aim to discuss their strengths and limitations, in relation to their current development and suitability as outcome measures for use in a clinical setting and as in upcoming drug trials in DMD. Duchenne muscular dystrophy (DMD) is a X-linked myopathy caused by the deficiency of dystrophin protein. Without dystrophin, muscle fibers are gradually replaced by connective and adipose tissue and progressive weakness and atrophy of locomotor and respiratory muscles arise . The proSpirometry is recommended by current guidelines for routine lung function evaluation in DMD ,12, sincBreathing occurs because respiratory muscles work together to generate pleural pressure swings that drive expansion or contraction of the chest wall and, thus, pump air (flow) in and out of the lungs ,15. The The respiratory muscles are the engine that generates the pressure gradient that moves the air in and out. According to the direction of the flow, they can be inspiratory  or expiratory . With their contraction, both the diaphragm and the abdominal muscles increase abdominal pressure contributing to change the volume of the abdomen, although with opposite effects. The diaphragm contracts during inspiration, making the abdomen expand, while abdominal muscles contract during active expiration, shrinking the abdomen. Rib cage muscles act on the ribs through the pump and the bucket handle movements. All ribs upon inhalation will externally rotate and elevate, therefore expanding the thorax. The opposite occurs during exhalation. Measuring thoraco-abdominal volumes might be highly informative as well. In the last decade, structural and functional characteristics of the respiratory muscles can be directly detailed by different imaging techniques, like ultrasound (US) and magnetic resonance imaging (MRI) ,19,20,21All the non-invasive techniques that assess these parameters of interest are described in the following section.The lung volumes of clinical interest are either capacities  or variation of volume. The latter are assessed through spirometry, being part of the routine pulmonary function testing, used to assess the general respiratory health. Spirometry measures the maximal inhalation and exhalation volumes of air as a function of time via a spirometer. Traditional parameters include forced expiratory volume in 1 s  and forced vital capacity . In contrast to FVC, slow vital capacity (SVC) measures the maximum amount of air that can be exhaled after a maximum inspiration, without requiring a forceful maneuver. Thus, it is ideal in patients who may have difficulty in performing forceful maneuvers . The meaMaximum static pressures measured at the mouth represent a simple assessment of global respiratory muscle strength . MaximalFlow of interest can be measured during forced vital capacity, but also during cough. Peak expiratory flow (PEF) is the maximal value reached during the force exhalation and it is a useful measure to assess respiratory function, in particular the degree of obstruction in the airways, but it also depends on the strength of the respiratory muscles. Peak cough flow (PCF) is the peak flow generated during a cough maneuver, after complete inhale, measured by a pneumotachograph or a peak flow meter connected to a facemask or a mouthpiece. PCF has been used to assess airway clearance capability and expiratory muscle function, and a threshold of 270 L/min has been adopted below which airway clearance is inadequate and assisted airway clearance is needed .The lung clearance index (LCI), derived from the multiple breath washout (MBW) technique, is a measure of overall lung ventilation inhomogeneity, calculated from the relative ventilation required to clear a tracer gas from the lung. LCI can be measured at any age in tidal breathing, without forced breathing maneuvers. Nevertheless, clinical measure of LCI is not routinely performed as time-consuming protocols are required, including at least three MBW runs with tracer gas washout until 1/40th of its starting concentration .Transcutaneous measurement of carbon dioxide pressure (Pco2) and pulse oximetry are non-invasive techniques that offer continuous monitoring over several hours by means of a transcutaneous sensor, which is placed on a membrane on the skin, commonly a digit, an ear, or the forehead. The gold standard to diagnose sleep-disordered breathing is polysomnogram. However, due to the limited access to polysomnograms, oximetry and capnography are also used in clinical practice. The overnight recording of Pco2 and oxy-hemoglobin saturation (SpO2) can determine whether a patient meets the criteria for nocturnal hypoventilation. However, it is not able to differentiate among types of sleep-disordered breathing. Hypercapnia is defined as Pco2 > 50 mmHg for 25% or more of the recording time , even ifDuring quiet breathing, the ventilatory pattern can be recorded breath-by-breath, by measuring the temporal trend of flow, using flowmeters, or volume.The lung volume is the integration of the flow signal. The chest wall volume can be directly measured in a precise way through optoelectronic plethysmography (OEP) or estimated by respiratory inductive plethysmography (RIP) or by structured-light plethysmography (SLP). OEP is a motion capture system that accurately measures the thoraco-abdominal contribution to tidal volume, detecting the 3D displacement of a large set of reflective markers placed on the thoraco-abdominal surface of the patient via infrared TV cameras, using dedicated geometrical models ,40. RIP In case of hypoxemia and hypercapnia, the body attempts to recover by increasing both tidal volume and respiratory rate. Breathing frequency is therefore an important sensitive indicator of increasing respiratory difficulty . RecentlThe chest wall is anatomically composed of two compartments: the ribcage and the abdomen. The tidal volume, therefore, is the sum of the volume variation of these compartments. OEP, RIP and SLP automatically provide thoraco-abdominal volume variation over time, as well. OEP is based on the anatomical definition of the two compartments since markers are placed according to anatomical points. Ribcage volume is therefore obtained as the volume enclosed by the clavicles and the lower costal margin; abdominal volume as the volume enclosed by the lower costal margin and the iliac crests . SLP ideUS imaging allows to non-invasively study the diaphragm at rest. Using an anterior subcostal view, the diaphragm is identified as a single thick echogenic line and the excursion of the diaphragm as shown in M mode, can be measured, during tidal breathing, deep inspiration or sniff maneuvers. Using a high frequency linear probe positioned perpendicularly to the chest wall in the intercostal space around the eighth rib, the diaphragm is outlined by two clear bright parallel lines, corresponding to the pleural and peritoneal membranes. Diaphragm thickness is estimated as the distance between the two lines. During inspiration, the diaphragm thickens because of muscle contraction. The thickening fraction can be therefore calculated as the difference between end-inspiratory thickness and end-expiratory thickness, and expressed as percentage of end-expiratory thickness ,20,56,57On MR images, the lungs can be directly imaged in 2D or 3D using both a static and dynamic acquisition. Using static MRI, lungs volumes and maximum vertical and antero-posterior lung diameters, as well as their changes from expiration to inspiration can be measured ,60,61. BMRI can be also used to directly image pathological muscle changes using multi-sequence imaging protocols, including T1-weighted and T2-weighted spin echo sequences, as well as fat-suppressed T2-weighted sequences (T2WFS). To quantify muscle involvement, scoring scales, from normal appearance to complete fatty degeneration, have been proposed ,67. NeveMRI provide a direct measure of both respiratory muscles structure and function. However, contraindications to MRI such as metal implants, invasive ventilation, and claustrophobia make it impossible to scan certain patients.With the disease progression in DMD, the respiratory muscles become weaker and taking a deep breath becomes harder for patients. Inspiratory reserve volume consequently reduces resulting in a lower total lung capacity (TLC). Moreover, exhalation is limited by the progressively acquired decreased chest wall compliance, producing a higher residual volume (RV). Forced vital capacity (FVC) is the most widely used outcome measure to assess respiratory function. Being the difference between TLC and RV, FVC is a global measure of both inspiratory and expiratory muscles’ function as well as chest wall stiffness. In DMD, FVC peaks between ages 10 and 14 years, whereas FVC%linearly declines, with variable rates depending on the age range of the patients included in the study ,73,74,75On dynamic MRI, lung cross sectional area was reported smaller in patients than in controls at both tidal and maximal inspiration and expiration ,64,65. TIn the absence of obstructive lung disease, PEF has been demonstrated highly reliable in DMD (coefficient of variation about 7%), and therefore highly valuable to assess expiratory muscle strength . Yearly In patients with DMD, minute ventilation progressively declines in supine position, significantly after the age of 18 years . PatientThe abdominal contribution to tidal volume during awake resting inspiration progressively decreases with age in supine position starting at the age of 15 years ,81, but In a group of 45 patients with DMD aged 5–25 years old, it has been demonstrated an increased ventilation inhomogeneity associated with the progressive decline in lung volume, with the retention of airways secretion and/or altered geometry suggested as possible causes .Sleep related hypoventilation in DMD, which precedes daytime hypoventilation, is due to both decreased ventilatory drive and respiratory muscle weakness and often obstructive sleep apnea, related to upper airways weakness, coexists ,87,88,89In a group of 64 DMD patients aged 10–18 years, Meier et al. reported high coefficients of variability for MIP (18%) and MEP (15%), irrespective of age, reflecting the patients’ difficulties of reliably reproducing these measures . MIP andIn patients, excursion amplitude during quiet breathing and sniff maneuvers on US are reduced, as well as excursion velocity during sniff maneuvers . On MRI,On US, diaphragm thickness in patients under 14 years old increases at FRC compared to healthy controls and reduces at TLC suggesting a decrease in diaphragm contractility, due to diaphragmatic pseudo-hypertrophy ,57. In oOn MRI, in a group of 36 individuals with DMD aged 7–19 years old, evidence of respiratory muscle pathology has been reported in early stages of the disease, when patients are still ambulant and highly functional . In partDMD progressively activates a cascade of events that starts from a structural change of the muscles and ends in their impaired function ultimately resulting in ventilatory failure as shown in Such structural damage induced by the dystrophy results in an impaired function, because of the loss of contracting units, with reduced diaphragm excursion and ventro-dorsal lung expansion ,63,64. ARegular monitoring of pulmonary function and gas exchange is crucial in patients with DMD, to recognize early symptoms of sleep-disordered breathing, daytime hypoventilation, and inefficient cough and swallowing ability and to timely implement the appropriate treatments. Guidelines for the respiratory management of DMD indicates lung-volume recruitment techniques, manual and mechanically assisted cough and non-invasive ventilation support as critical therapies ,11. ThesLung volume recruitment technique is undertaken by using a self-inflating manual ventilation bag or mechanical insufflation/exsufflation once or twice daily and is indicating when FVC is lower than 60% of predicted. Lung volume recruitment has demonstrated to improve respiratory system compliance  and to s2O indicative of effective cough [Ineffective cough and consequent retained secretion is the main cause of episodes of pneumonia and acute respiratory failure, secondary to benign upper-respiratory infection. Studies have identified a peak cough flow (PCF) of 160 L/min as threshold value for starting cough-augmentation therapy . Howeverve cough . Additiove cough . More reve cough . When asve cough . A greatve cough . Compareve cough . The expve cough . Studiesve cough ,118.2 (>50 mmHg for 2% of sleep time or increased by 10 mmHg from awake baseline) and SpO2 (≤88% for 2% of sleep time or for at least 5 min uninterrupted). Several studies investigated the sensitivity of spirometry parameters to respiratory muscle weakness, which could be useful as daytime predictors of sleep breathing related disorders and indicators for establishing nocturnal non-invasive ventilation [2 < 95%, pCO2 > 45 mmHg, or symptoms of awake dyspnea are present [Nocturnal ventilation is indicated when signs of insufficient pulmonary function are present during sleep. Initial recommendations for initiation of non-invasive ventilation were based on daytime hypoventilation , but gratilation ,89,120, tilation ,122. Mortilation . In the  present . The tra present ,124, but present ,126,127.Swallowing deficit should be also evaluated in patients with advanced disease, as it represents the principal cause for decreased oral intake and it is closely associated with bulbar muscle function. A significant interaction has been reported between respiratory muscle strength, evaluated by measuring MIP and MEP, and both nutritional parameters  and the There is currently no definitive cure for DMD, but the field of DMD therapy is advancing very quickly. The choice of primary and secondary outcome measures to evaluate the efficacy of clinical trials is crucial. Outcome measures should be quantitative, sensitive to longitudinal changes, safe and repeatable. Moreover, outcomes strongly related with quality of life, such as initiation of non-invasive ventilation or number of recoveries/year due to respiratory infections, render the findings of the studies clinically meaningful.The current standard of care for DMD consists of corticosteroids , which hIdebenone, an antioxidant that improves mitochondrial energy production, demonstrated the reduced loss of respiratory function in patients with DMD . ResultsNew therapies to increase dystrophin production in small genetic subsets of DMD have recently been approved. Ataluren in EU and eteplirsen in US are the first mutation-specific therapies to gain regulatory approval and others are under development or near regulatory review. The effect of ataluren on lung function has been investigated in a prospective study including four patients and no statistically significant improvement/stabilization was detected . More reCurrently, FEV1, FVC and PEF are the respiratory measures included as primary and secondary outcomes in clinical trials . In addition, MIP, MEP and SNIP have been included as outcomes in trials investigating the effects of different physiotherapy programs, to determine respiratory muscle strength . Interestingly, respiratory muscle MRI is currently included as secondary outcome in a study on the potential of noninvasive MRI to monitor disease progression and to serve as an outcome measure for clinical trials in muscular dystrophies (NCT01484678) .Different outcomes have been demonstrated useful to monitor respiratory disease progression, to be used to plan individual respiratory management and to evaluate novel therapies.The more traditional measures, such as maximal pressures, flows and volumes have an almost linear decline starting from early childhood and therefore it is difficult to identify specific time points that represent milestones for respiratory clinical management. As effort-dependent measures, they require patient cooperation, coordination and motivation and therefore cannot be performed in early childhood and late adolescence. Moreover, they represent measures of overall respiratory impairment and their decline results from the interaction between respiratory muscles, lungs, airways resistance and chest wall compliance. Nevertheless, these measures are highly available and reproducible across clinical centers and studies on the natural progression of respiratory function decline are available ,77, makiOver these measures, the evaluation of breathing pattern and thoraco-abdominal volumes are effort-independent and well suited for the evaluation of respiratory function starting from early childhood. Moreover, studies on the natural progression of these outcomes over time are available. They have demonstrated sensitivity to early ventilatory insufficiency, and they represent highly valuable outcomes to guide clinical management, providing milestones to start cough assistance and nocturnal ventilation ,83,84. NImaging techniques provide specific measures of structural and functional impairment of respiratory muscles. Ultrasound, as an effort independent technique, may be particularly interesting for use in clinics and for experimental trials, but the lack of standardization, the high intra- and inter-operator variability impede its widespread clinical use. Other ultrasound techniques such as strain imaging or elastography of the diaphragm, respectively sensitive to muscle contractility and stiffness ,145,146,Respiratory function has been only recently included as primary outcome in clinical trials and this is particularly important, as respiratory failure is among the main causes of death in DMD. An increased number of studies have proposed novel non-invasive measures for respiratory assessment and research for standardizing protocols across different centers is ongoing. The development of measures aimed to specifically understand the separate involvement of the different actors of breathing, may provide a tool not only for evaluating clinical trials, but also to guide clinical decisions from the early stage of the disease.


The Impella 5.5 SmartAssist  is a surgically implanted temporary device, recently approved by the FDA , blood pressure 80/35 mmHg, right ventricle dysfunction, severe pulmonary arterial hypertension (an estimated systolic pulmonary artery pressure of 45 mmHg), and severe mitral valve regurgitation. Second patient was admitted for massive MI with large anterior VSD (Qp/Qs ratio of 2.8). Under cardiopulmonary bypass with cardioplegic arrest both patients underwent urgent VSD closure with trans-aortic implantation of the Impella. Minimal postoperative support was required. Patients were discharged on postoperative day 10 and 14 and remained well 3 months later. Follow-up echocardiogram showed no residual shunt.Early surgical implantation of Impella 5.5 SmartAssist can prevent multiorgan dysfunction and stabilize the patients in cardiogenic shock with post-myocardial infarction VSD.The online version contains supplementary material available at 10.1186/s13019-021-01513-y. Despite advances in surgical techniques and aggressive therapy including ventricular assist devices (VAD), the overall morbidity and mortality is frustratingly high. The timing of surgical intervention is critical. Moreover, no guidelines have been established for patient selection for early use of VADs in this setting. The Impella 5.5 with SmartAssist  is a surgically implanted temporary VAD recently approved by the FDA for treatment of patients in cardiogenic shock, and may fill a technology gap for perioperative patients who require acute circulatory support Fig. a,b. ThisA 59-year-old man presented to our institution with acute inferior MI and low blood pressure. Examination revealed a loud systolic murmur. Transthoracic echo demonstrated a large posterior VSD with a significant shunt (Qp/Qs ratio of 3.3), right ventricular dysfunction, severe pulmonary arterial hypertension, and akinesia of the inferior wall. Severe mitral valve (MV) regurgitation was observed. Coronary angiography displayed normal left main stem, 100% RCA occlusion, and 40% mid LAD stenosis. RCA has diffuse lesions with severe distal disease and was not graftable. Cardiac index was 1.7 and a chest X-ray revealed pulmonary edema. The patient was diagnosed with inferior MI and a large posterior VSD with cardiogenic shock (< 80/40 mmHg), and underwent urgent VSD repair.Under cardiopulmonary bypass (CPB) with cardioplegic arrest, left ventriculotomy was made. A posterior VSD measuring 3.5 × 4.5 cm in diameter was found Fig. c. The seVideo S1Minimal postoperative support was required (epinephrine at a dose of 0.02 μg/kg per min). Right ventricular (RV) load declined, as depicted by decreasing RV dimensions Table . The devA 60-year-old male was admitted for massive anterior MI with cardiogenic shock (CS). Work-up showed proximal LAD occlusion, a large anterior VSD with a left-right shunt (Qp/Qs ratio of 2.8) and ejection fraction of 25%. Despite intra-aortic balloon counter pulsation and inotropic support, the patient developed shock with cardiac index of 1.8 and serum lactate of 6 mmol/L. In the operating room, a ventriculotomy was performed. The VSD  is commonly used in such patients; however, ECMO has been shown to compromise LV contractile function with increased LV end-diastolic pressure, LV afterload, impaired myocardial blood flow and the frequent need for an additional intervention such as LV venting. In cases of advanced cardiogenic shock with severe RV dysfunction and multi-organ failure, we have previously utilized ECMO with Impella support. The Impella 5.5 SmartAssist provides more practical and effective postoperative treatment and mechanical support and could facilitate post-operative treatment in patients with LV dysfunction with myocardial stunning. In the case of significant RV failure, one should consider adding RVAD, avoiding the need for ECMO, especially in the lack of severe systemic malperfusion.With a forward flow to the systemic circulation of up to 6.2 L/min the Impella 5.5 is best able to decompress the heart of all currently available mechanical circulatory support devices used in the setting of cardiogenic shock. This is particularly important in patients with large body habitus or in cardiogenic shock with a vasodilatory component, which may be exacerbated by suboptimal LV decompression. Other features of the Impella 5.5 SmartAssist include the potential for device removal and repositioning at bedside; furthermore, in our cases we observed an improvement in RV function with resolution of pulmonary edema. These findings may lower the decision threshold for an early surgical approach and the initiation of mechanical circulatory support restoring the hemodynamics, preventing the aggravation of organ failure and potentially leading to improved outcomes in patients with post-infarction VSD in cardiogenic shock.To our knowledge, this is the first report of surgical implantation of the Impella 5.5 SmartAssist for patients with post-infarct VSD in cardiogenic shock. Our experience suggests the feasibility of using the Impella 5.5 SmartAssist to stabilize the patient, lowering pulmonary arterial and wedge pressure, reduce mitral valve incompetence and support the stunned ventricle with improvement of cardiac index after early surgical VSD closure. This strategy allows for heart recovery while maintaining distal organ perfusion. Our findings concerning the unique utility of the Impella 5.5 in the setting of cardiogenic shock in patients with post-MI VSD merit broader exploration. We should carefully evaluate these critically ill patients. Depending on the degree of right ventricular failure and systemic malperfusion, we should consider other circulatory support strategies.


Cardiotoxicity is a well‐known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol.Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software‐specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects.We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and ≥2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra‐class correlation coefficients for inter‐observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra‐class correlation coefficients for intra‐observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr.The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high‐quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters. The most frequently reported systolic function parameter, left ventricular (LV) ejection fraction (LVEF), is considered the standard echocardiographic measure of LV dysfunction but is a rather late marker compared with measurements of myocardial strain.The Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort (1963‐2001) part 2; clinical visit and questionnaire study provides a unique opportunity to investigate cardiotoxicity, next to various late effects in a large sample of very long‐term survivors (DCCSS LATER 2 CARD study). This substudy includes solitary and combined analyses of echocardiography, electrocardiograms, and blood biomarkers.As myocardial strain analysis is very comprehensive and results are influenced by the software and definitions used, it is of key importance to describe the methods in detail. Furthermore, the feasibility of (strain) measurements should be described, as they depend on image quality. Last, the measurements should be reproducible in research and clinical follow‐up. The overall design of the DCCSS LATER 2 CARD study has recently been published.22.1The cross‐sectional DCCSS LATER study part 2 investigates late treatment effects in a nationwide cohort of 5‐year CCS, treated under the age of 18 years between 01‐01‐1963 and 31‐12‐2001.2.2Pediatric and adult cardiologists developed the echocardiography protocol, in collaboration with the DCCSS LATER 2 CARD steering committee and the Dutch childhood cancer cardiac consortium.2.2.1Experienced sonographers acquired images on the locally available Philips (8%) or GE (92%) stations. Table 2.2.2Images were locally stored and pseudonymized. Raw DICOM files were transferred to our echocardiography core laboratory at the Radboud university medical center, Nijmegen, via protected storage‐ or exchange media. Extraction of our offline measurement results from the analysis software was automated using custom scripts, and the data were then imported in a web‐based database .2.2.3For reader convenience, we refer to conventional  and strain measurements. Echocardiograms obtained for standard care were analyzed by the sonographer and an imaging cardiologist. For “research‐only” echocardiograms, only images (without online measurements) were stored. All measurements were (re)performed offline at the core laboratory by one out of two observers (RM or JL). The observers were blind for all participant information such as previous cancer diagnosis, therapy modalities and doses, cardiovascular risk factors, electrocardiographic findings, and blood tests. Analysis of conventional parameters for research‐only participants was performed upon receipt in the core laboratory, to be able to report unexpected findings  to their own physician within six months, as indicated by the ethical committee. Strain analyses were performed at a different time point, blinded from clinical information, and conventional echocardiographic measurements.Conventional measurements were performed in EchoPac 202  for GE acquired images, or TomTec Arena 2.31  for images from Philips stations. Myocardial strain analyses were performed using the vendor‐independent TomTec 2D Cardiac Performance Analysis software v1.4. We expect minimal impact of the different image acquisition stations on the strain results, as >90% of the images were acquired on GE stations.Observers subjectively rated the overall image quality  of an examination as “good,” “fair,’ “moderate,” or “poor,” allowing sensitivity analyses for the study results. When available, left ventricular dimensions were measured on 2D parasternal long‐axis images rather than M‐mode, to prevent oblique measurements.2.2.4The cardiac cycle with the best image quality was selected. For all cardiac chambers, end‐diastole was set at the QRS‐peak to pursue the highest reproducibility.Endo‐ and epicardial 15‐point contours were manually applied to the LV wall in end‐systole, tracked by the software and, if necessary, manually adjusted in end‐diastole to cover the whole cardiac wall. Tracking quality was visually confirmed based on the superimposed grayscale images and the typical curve morphology. If tracking was inadequate, the contours were iteratively adjusted.Endocardial longitudinal strain of the RV was preferably measured from a RV focused apical four‐chamber view. To anchor the tracking of the RV apex, the interventricular septum was tracked, but then excluded to report the RV free wall longitudinal strain. Discarding of one of the three RV free wall segments was accepted when inadequately tracked. Endocardial longitudinal strain of the LA was measured from a non‐foreshortened apical four‐chamber view. As no segmentation applies to the LA, no segments could be discarded and global strain is calculated.Left ventricular GLS was calculated as the mathematical average at end‐systole of the 18 segments derived from the three apical  views,Global circumferential strain (GCS) was measured in short‐axis view at the papillary muscle (mid‐ventricular) level and was averaged over six segments.Left ventricular mechanical dispersion, an important prognosticator for ventricular arrhythmias in multiple cardiac diseases,2.3All sonographers on‐site were familiarized with the protocol. The two core‐laboratory observers were physicians and extensively trained and supervised by (pediatric) cardiologists with established experience in echocardiography and strain . When observers doubted on endocardial border definition, quality of Doppler signals, severity of valvular dysfunction or presence of cardiac anomalies, studies were over‐read by LKa.2.4Primary study endpoints were previously defined,2.5The feasibility of the primary outcomes of systolic and diastolic function and all strain analyses is presented as a percentage of all analyzed echocardiographic examinations. Differences in proportions between CCS and siblings were analyzed using Pearson chi‐square test. Core laboratory inter‐ and intra‐observer variability was tested in 30 randomly selected participants with sufficient image quality for the measurement concerned . Intra‐observer measurements were at least two weeks apart. The same cardiac cycle was used to exclude any temporal variability. Intra‐class correlation coefficients  and Bland‐Altman plots showing absolute and relative mean differences between observers and limits of agreement  are presented as measures of agreement. The higher the ICC, the smaller the required sample size. With a probability of a type I error set at 5%, a sample of 30 patients provides a power of 91% to distinguish an ICC of 0.75 (good‐excellent) from 0.4 (poor), and 95% to distinguish and ICC of 0.9 from 0.7.33.1As from the study closure date on March 1, 2020, protocolled echocardiograms of 1,618 participants were available in our core laboratory. Of these, 1,341 echocardiograms were obtained in CCS and 277 in sibling controls. We found 61 additional echocardiograms from CCS in risk group 1 to contain images compliant with our protocol, resulting in a total of 1,679 echocardiograms. A detailed inclusion flowchart is depicted in Figure 3.23.2.1P=.530). Feasibility of the primary outcome measurements and strain measurements is shown in Table P =.006), diastolic function in 99% and 100% (P =.10), respectively, and GLS in 80% and 91% (p = <0.001). All 18 segments were included in 75% of the GLS calculations in CCS and in 74% of those in siblings (P=.64).Image quality was rated ‘good” in 606 36%), ‘fair’ in 793 (47%), “moderate” in 245 (15%), and ‘poor’ in 35 (2%) of the participants. Image quality did not differ between CCS and siblings . Proportional biases for diastolic septal thickness and fractional shortening could not be excluded , but resolved when deleting two highly influential extreme datapoints. Relative to the mean value, the limits of agreement were wide for LV mechanical dispersion (−53 to 43%), septal and posterior wall thickness , left atrial volume (−47 to 34%), and fractional shortening (−29 to 49%).The core laboratory inter‐observer variability in a subset of 30 participants is depicted in Table Intra‐observer analysis Table  generall4This echocardiography protocol of the Dutch nationwide DCCSS LATER 2 CARD study is unique in its comprehensiveness incorporating well‐established conventional echocardiographic parameters on systolic and diastolic performance, as well as advanced quantification of myocardial function using strain measurements obtained in vendor‐independent software. We show high feasibility and reproducibility of the measurements, which will support the generalizability of the conclusions from our main outcome analyses.In a comparable cohort from the St. Jude Lifetime Study that included 1,820 adult long‐term CCS, Armstrong et al evaluated cardiotoxicity in CCS during an outpatient clinic visit with echocardiography. This study also provided a very detailed cardiac assessment including LVEF, GLS, and GCS as systolic function parameters, diastolic function indices and exercise capacity.4.1The feasibility of the (advanced) echocardiographic measurements was higher in sibling controls than in the participating CCS. Although our overall image quality rating was not different between CCS and siblings, it might not be robust enough to detect subtle differences. The feasibility of measurements itself may be regarded as a more objective and detailed manifestation of individual image quality. There may be a number of reasons for this difference. First, image quality might be affected more often in CCS, due to consequences of radiotherapy exposure or surgery on the chest region, and different body composition. Second, siblings were invited in a later stage than CCS, when sonographers and centers may have been better familiarized with the acquisition protocol. Of note, the core laboratory measurements did not start before siblings were included, to ensure blinding.Third, to prevent missing CCS with less frequent surveillance or with more severe cardiotoxicity, we included some additional echocardiograms as stated in the methods section.Nevertheless, the feasibility of GLS measurement in 80% in the context of an acquisition protocol is comparable to that of the Normal Reference Ranges for Echocardiography study.4.2Generally, the inter‐observer variability of conventional and strain measurements in the present study lies within the ranges reported in the literature.First, the reproducibility of biplane LVEF is comparable to that of GLS, which we attribute to the use of the semi‐automated endocardial border tracking option for LVEF measurement. This functionality is based on speckle tracking and minimizes user interaction, which has been shown to reduce inter‐observer variability and the need for expert readers, compared with manual contouring.Second, we chose not to include global radial strain (GRS) in our protocol. GRS has been reported to have inferior reproducibility compared to GCS,Notably, LV mechanical dispersion showed acceptable ICCs for inter‐ and intra‐observer variability, but with wide limits of agreement  relative to the measured values. These limits of agreement are accepted in the field, as differences of 20msec were shown relevant for predicting arrhythmias.4.3Myocardial strain imaging has not been fully adopted by the chamber quantification guidelines,A major perceived limitation in using strain measurements is the heterogeneity in proposed cutoff values that are provided by the different software vendors. Variability in published strain values may furthermore depend on event timing and the myocardial layer that is analyzed. A dedicated task force is in place to standardize strain measurements,We have provided a detailed description of our myocardial strain measurements, including the handling of not‐tracked segments and GLS calculation, which are important for reproducibility and fair comparisons to normative values.4.4Although LVEF measured on three‐dimensional echocardiography proved to be more reproducible and thus more suitable than biplane LVEF to detect subtle changes over time,5The echocardiographic substudy of the nationwide cross‐sectional DCCSS LATER 2 CARD study evaluates the prevalences of contemporary systolic and diastolic function parameters in a large cohort of CCS and has a parallelly included sibling cohort for comparison. It includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements.None declared.LKr, JLo, CR, WT, MvdHei, HvdP, EvDa, EvDu, MvdHeu, AdV, ML, EF, LKa, YP, CdK, GW, LB, AMaa, and AT involved in concept / design. LKr, JLo, WK, AMav, EF, LKa, YP (Dutch Heart Foundation); LKr, EvDu, MvdHeu, and WT (KiKa/ODAS) involved in funding. RM, JLe, and GW involved in data collection and database management. RM, JLe, and LKa involved in statistics and data analysis. RM, LKa, and WK involved in drafting article. All listed authors involved in interpretation, critical revision, and approval of article.Figure S1. Feasibility of measurements depicted for different image qualities. Examples of a B‐mode (LVEF = left ventricular ejection fraction), an M‐mode (TAPSE = tricuspid annular systolic plane excursion) and a speckle tracking  measurement are shown.Click here for additional data file.


The transcatheter mitral valve prosthesis is ideally suited for patients with inoperable mitral etiology. The transcatheter mitral valve implantation (TMVI) procedure has closely followed the evolution of transcatheter aortic procedures. There are considerable design variations amongst the limited TMVI prostheses currently available, and the implantation profiles of the devices are notably different. This comprehensive review will provide an overview of the current clinically tried TMVI devices with a focused outcome analysis. In addition, we have discussed the various design characteristics of TMVI and its associated failure mode, implantation technology, delivery methods, first-in-man trials, and pivotal trial summary for the synthesis of recent evidence.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255241, identifier: CRD42021255241. Mitral regurgitation (MR), also known as mitral insufficiency or incompetence, is a leading cause of death worldwide; in western countries, where rheumatic heart disease has a low prevalence , MR remaun avenir prometteur since its inception . Transcatheter mitral valve treatment (TMVT) shows nception , despitenception . TMVT conception , whereasnception . In contnception , especianception . Surgicanception . Howevernception .The prosthesis design of the current TMVI devices may hinder the heart's dynamic function, especially during diastole; it may also lead to increased transmitral gradient and reduced effective orifice area (EOA), leading to clinical problems . Left veAdditionally, prior TMVr procedure addressing the valve leaflets limits the use of the TMVI device despite the potential necessity. Currently, mini-thoracotomy and transapical TMVI access remain mainstream in approaching the native mitral valve . The delHerein, we provide a comprehensive overview of the TMVI devices focusing on the clinical outcomes of first-in-men (FIM) clinical trials. In addition, we discuss the design variation and optimization potential with failure modes of the devices, as required for regulatory approval.Inspired by an old bottle stopper, Albert Starr developed the “Ball-cage” prosthesis design, which was the first mechanical heart valve implanted in the mitral position in 1961 . The StaThe biological valve was a cause of concern due to inert complications recognized from the metallic devices. The biological valve has its advantages in terms of better biocompatibility with questioned durability. The porcine formalin-fixed xenografts were first used by Carpentier in the mitral position in 1965 , shortlyThe first catheter-based procedure for mitral stenosis was percutaneous balloon mitral commissurotomy (PBMC); Inoue first used trans-femoral and trans-septal balloons in 1984 , which hvia transseptal access. Transapical catheter-based procedures were subsequently extended to treat degenerated bioprosthetic valves with valve-in-valve and valve-in-ring procedures by 2014 , Embase, Cochrane Library, Scopus, and Web of Science from inception to May 30, 2021.We conducted a database search for published literature electronically using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines . The litA repetitive and exhaustive combination of the following “medical subject headings” (MeSH) were used: “mitral valve replacement,” “mitral valve implantation,” “transcatheter,” “transcutaneous,” “systematic review,” “transcatheter mitral valve replacement,” “transcatheter mitral valve implantation”. This study protocol has been registered with PROSPERO (CRD42021255241). Relevant articles were screened and systematically assessed, applying inclusion and exclusion criteria.in vitro experiments and animal experiment studies were excluded.Studies were only included if published in English, and any experimental cohort studies in humans reporting first and early clinical trials reporting the use of TMVI for mitral valve disease were included. Valves designed and implanted in other cardiac positions were beyond the scope of this study. Mitral valve repair devices for TMVr were also beyond this scope. Furthermore, only studies published after 2010 were included to prevent using nonrelevant data. Articles with TMVI and other concomitant cardiac procedures and nonclinical via Pubmed). Further data were sought by manual search using the backward snowballing method.The extracted citations were screened and assessed by using the reference manager software EndNote X9 independently for inclusion. The articles were first screened by their titles and abstracts, where criteria were purposely broadened to include all relevant studies. Second stage review for studies that have made it through the first stage, or cases where a decision cannot be made, full-text reviews were performed on articles to confirm the relevance. To improve the sensitivity, we have used citation chasing in Google Scholar and Medline  . DependiAll the included studies were prospective observational study with the majority reporting the first-in-men clinical trial. As illustrated in chapter 11 of the Cochrane handbook of reviews , GradePrThis systematic search revealed a total of 5,219 articles and systematic reviews. Two other papers were retrieved from alternative sources. After exclusion of the duplicates, 3,082 articles remained for assessment. Irrelevant publications that did not satisfy our inclusion criteria were not considered based on title and abstract scrutiny, leaving 208 articles for full-text review. Following the full-text assessment of these articles, 12 papers –53 remaiAs seen from All studies were First-in-man clinical trials, reporting data on TMVI replacement in single –51, 53 oTwelve manuscripts –53 that via apical access (through mini-thoracotomy), some were trans-septal, and the use of both approaches has been observed as well. Several devices were in the pipeline and found to be at different stages of development; this is summarized in Design variations, including size, annular shape, anchoring mechanism, access, and recapture features, have been summarized in The majority of the included studies reported a high procedural/technical success rate, even though each of the device was unique in terms of its design variation; this is summarized in Most of the patients were discharged home after successful implantation of the TMVI devices, with a few reintervention during index hospitalization . Two patThe average age of the included patients was >75 years with high STS  and EuroScore-II . Most of the patients were NYHA III/IV with multiple comorbidities. Around 38% of the patients had prior coronary artery bypass graft surgery (CABG), and 10% had other cardiac procedures, as Bapat et al.  reportedDesigning a TMVI device is a challenging task, and the design variation of the currently available devices shows the magnitude of the anticipated difficulties. Various new stent design approaches were developed to address LVOTO, valve anchoring, sealing, and dynamic deformation of the mitral annulus throughout the cardiac cycle. The key findings of this systematic review are been summarized in via its design as a fully supraannular stent . Multiple factors increase the risk of LVOTO, including an obtuse aortomitral angle, degree of septal hypertrophy, and left ventricular size . Additioar stent . Highlifar stent .via various measurements such as, but not limited to, intercommissural diameter, anteriorposterior distance, and mitral annular perimeter. Adequate sizing draws a balance between oversizing for anchoring and fixation, described in the implantation of Intrepid and Altavalve while minimizing the risk of LVOTO  includes incorporating an atrial fabric skirt sewn into or outside the expandable nitinol frame , 48, 53.via valve-in-valve (VIV) approach in degenerated bioprostheses or severe MAC patients  patients –66. Thispatients . The morHowever, the mitral valve is larger than the aortic valve, provides less support, and is much more asymmetric in shape, which has made the use of TAVR devices in the mitral position to valve in ring (VIR) procedure quite challenging. Fortunately, unlike the saddle-shaped native mitral annulus, the old prosthetic valve creates a circular morphology in which devices initially designed for aortic valve replacement can be implanted. Devices such as Sapien M3 were readily available commercially on account of established success in TAVR and are well studied in the literature. Direct flow has currently been discontinued; Inovare and Sapien M3 continue their clinical trials specifically for implantation in the mitral area . Mi-ThosThere are several access strategies for TMVI, including transapical, transseptal, or hybrid . The mosvia the transseptal route, e.g., Sapien M3, Cephea Altavalve, Cardiovalve  disclosed receipt of the following financial support for the research and publication of this article. This work was supported by the National Research Foundation (NRF), Singapore, Central Gap Fund (NRF2020NRF-CG001-018).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.


The results of ROC curves showed that T3 LAVmin had the most diagnostic efficiency of cardiotoxicity . Detection of changes in left atrial volume using three-dimensional ultrasound could be used as strong predictors of cardiotoxicity caused by anthracycline chemotherapy drugs in patients with multiple myeloma.In order to study the value of left atrial volume three-dimensional echocardiography in predicting cardiotoxicity in patients with multiple myeloma undergoing anthracycline chemotherapy, a total of 53 patients with multiple myeloma who are treated in the Department of Hematology of our hospital from January 2018 to December 2020 are selected as the research object, and all patients underwent three cycles (T1–T3) of chemotherapy. Before and after each cycle of chemotherapy, the patients are examined with 3D ultrasound and serology detection. These patients are divided into the cardiotoxicity group and noncardiotoxicity group. The serological indexes and three-dimensional echocardiographic parameters between two groups are compared. Multivariate logistic regression is used to determine the independent risk factors of cardiotoxicity in patients undergoing chemotherapy. And ROC curves are performed to evaluate the diagnostic value of related indicators in predicting cardiotoxicity. A total of 53 patients with multiple myeloma are included in this study. Serological indexes (T3 cTnI and T3 Pro-BNP), T2 LAVmin, T3 LAVmin, T2 LAVprep, and T3 LAVprep in the cardiotoxicity group are significantly higher than those in the noncardiotoxicity group. Multivariate logistic regression further found that T3 cTnI, T3 Pro-BNP, T2 LAV Multiple myeloma (MM) is a hematological malignant disease, caused by an uncontrolled clonal proliferation of plasma cells. The major characteristics of MM are an overabundance of monoclonal paraprotein, the uncontrolled proliferation and extensive infiltration of malignant plasma cells, and the synthesis inhibition of normal polyclonal immunoglobulins, resulting in a series of clinical manifestations. Multiple myeloma could affect multiple organ systems including the hematopoietic system, bone, kidney, heart, liver, and nervous system, which seriously influences the life quality of these patients –4. CardiTherefore, in order to promptly adjust chemotherapy regimens, it is necessary for clinicians to take the detective measures and timely evaluation for cardiotoxicity in MM patients undergoing ANTs drugs. The changes of electrocardiogram and serological indicators, or a fall of LVEF >10% from the baseline EF value, are the common methods for assessing chemotherapy-related cardiotoxicity. However, these indicators are not suitable for the early prediction of cardiotoxicity . It is rThis study is approved by the Ethics Committee of The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, and all patients or their families provided written informed consent before research. The study included 53 patients aged 31–78 years with 30 males. These patients with multiple myeloma are scheduled to undergo anthracycline chemotherapy between January 2018 and December 2020.The study inclusion criteria are as follows: (1) the patients are diagnosed with multiple myeloma. (2) There is no history of other tumors diseases. (3) The patients are without thoracic deformity, respiratory disease, and other diseases significantly affecting the accuracy of ultrasound. (4) Before chemotherapy, LVEF indicator is normal in the examination of conventional echocardiography. (5) The estimated survival time is more than 2 years. The exclusion criteria are as follows: (1) the patients are with congenital heart disease, chronic coronary artery disease, myocarditis, and other diseases affecting cardiac function. (2) The patients are considered as cardiac dysfunction before chemotherapy through conventional echocardiography, electrocardiograph, and other laboratory tests. (3) Anthracycline or other drugs affecting cardiac function are used before.2 pegylated liposomal doxorubicin is intravenously injected on day 1; 1.3 mg/m2 bortezomib is intravenously injected on day 1, 4, 8, 11; and 20 mg dexamethasone is intravenously injected on day 1-2, 4-5, 8-9, 11-12. The chemotherapy is repeated every 3 weeks as a course. The patients have applied 3 courses of treatment. According to the chemotherapy cycle and checkpoints, the time points for examination are as follows: before chemotherapy (T0), the first cycle of chemotherapy (T1), the second cycle of chemotherapy (T2), and the third cycle of chemotherapy (T3).PDA  regimen is performed in all the patients with diagnosed multiple myeloma. During the chemotherapy cycle, 30 mg/mCTNI and NT-proBNP are cardiac markers detected in our study with a routine blood sample at different time points. The serum is separated from venous blood by centrifugation at the speed of 3000 rpm under the condition of 4°C. cTNI and NT-proBNP are assessed by the automatic biochemistry analyzer .min), maximum left atrium volume (LAVmax), left atrium volume before contraction (LAVprep), left atrium ejection fraction (LAEF), and left ventricular ejection fraction (LVEF). One cardiologist is blinded to patients' history, types of chemotherapy drugs administered, and biochemical markers and interpreted echocardiograms. Cardiotoxicity is defined as a fall of EF >10% from the baseline EF value during follow-up echocardiography. Definite diagnosis of cardiotoxicity is conducted during chemotherapy cycles. These patients are divided into the cardiotoxicity group and cardiotoxicity group according to the LVEF changes.All the patients underwent three-dimensional echocardiographic evaluation at different time points with an X5-1 probe and an application frequency of 2.0–3.5 MHz. All the evaluations are performed and analyzed with QLab software installed. The following indicators are examined: minimum left atrium volume (LAVt-test is used to determine differences between two groups. Count data are presented as rate (%) and are analyzed using the χ2 test or Fisher's exact probability test. Multivariate logistic regression analysis is conducted to explore the relationship between the cardiac risk factors and incidence of cardiotoxicity. The odds ratios (OR) and 95% confidence intervals (CIs) are obtained from regression coefficients. In addition, ROC curves are performed, and the diagnostic efficiency of these parameters is evaluated by the area under the ROC curve. P value ≤0.05 is considered a significantly statistical difference.The statistical analysis is performed using SPSS19.0 and MedCalc 22.0. Normally, distributed quantitative data are expressed as mean ± standard deviation (SD). The △LVEF >10% occurred one year after chemotherapy, these patients are divided into cardiotoxicity group (N = 10) and noncardiotoxicity group (N = 43). The incidence rate of cardiotoxicity in patients undergoing anthracycline chemotherapy is 18.87%. No significant differences in age, gender, BMI, thyroid disease, lung disease, and cardiovascular risk factors are found between two groups.In total, 53 cases of patients with multiple myeloma are included in this research, and their clinical and demographic characteristics are summarized in P < 0.05).The levels of cTNI and Pro-BNP are compared at different points during the follow-up period between two groups, as shown in min), maximum left atrium volume (LAVmax), and left atrium volume before contraction (LAVprep) of two groups continued to increase during follow-up. Compared with noncardiotoxicity group at T2 and T3 time points, LAVmin and LAVprep values in the cardiotoxicity group are significantly increased. And there are significant differences between two groups (P < 0.05). min, T3 LAVmin, T2 LAVprep, and T3 LAVprep are independent risk factors for predicting cardiotoxicity in patients with multiple myeloma undergoing anthracycline chemotherapy.The diagnostic values of these indexes in predicting cardiotoxicity in patients with multiple myeloma undergoing anthracycline chemotherapy are performed using multivariate logistic regression analyses. As shown in min, T2 LAVmin, T3 Pro-BNP, T3 LAVprep, T2 LAVprep, and T3 cTnI. Further study is performed to analyze the diagnostic efficiency of these indexes for predicting cardiotoxicity in multiple myeloma patients undergoing anthracycline chemotherapy using ROC curves. As shown in Anthracycline chemotherapeutics for treating MM patients could cause a loss of heart function and, in severe cases, affect the prognosis of these patients . TherefoReactive oxygen species including superoxide free radicals and hydroxyl free radicals are generated in the metabolism process of anthracycline chemotherapeutic drugs. Lipid molecules on the cell membrane surface are oxidized by hydroxyl free radicals, and it is helpful to generate malondialdehyde. The produced malondialdehyde could diffuse among cells and destroy important molecular structures in cells , 19. DueSerological indicators such as cTnI and Pro-BNP had certain advantages in the early prediction of myocardial injury because they are released into the blood after myocardial injury . ROC curThree-dimensional echocardiography is more accurate in evaluating the volume of the left atrium in contrast to conventional echocardiography. It could dynamically display the changes of various indicators for the left atrium volume in real time without depending on the geometric shape of the left atrium. The high sensitivity of three-dimensional echocardiography is reported in predicting cardiovascular adverse events.The physiological roles of the left atrium consisted of storage function, channeling function, and pump function, which played an important role in maintaining left ventricular filling. In the early period of diastole, the left ventricular filling mainly depended on the storage function and channeling function. And in the late period of diastole, initiative atrial systole depending on pump function is the key point for left ventricular filling. The mild or moderate left ventricular diastolic dysfunction usually led to increased pump function of the left atrium . Reducedmax, LAVmin, and LAVprep are closely correlated with the left ventricular diastolic pressure by analyzing the correlation between the left atrial volume indicators and the left ventricular diastolic pressure measured by transcardiac catheterization [max, as the left atrium volume at the end of the left ventricular systole, is not only affected by the left ventricular diastolic function but also by the longitudinal mechanical traction of the left ventricular myocardial fibers. LAVmin could directly reflect the left ventricular diastolic function without being affected by the left ventricular systolic function. This is because the left atrial pressure is basically equal to the left ventricular pressure due to the opening of the mitral valve in the left ventricle end diastole. For the evaluation of left ventricular diastolic function, LAVmin is more sensitive than LAVmax [min and LAVprep) had more advantages in assessing the degree of left atrium injury. This study also revealed that LAVmin and LAVprep gradually increased with the cycle of chemotherapy, and the differences between the groups are statistically significant, which suggested that the cardiotoxic effect of chemotherapy drugs led to reduced left ventricular diastolic function and had high sensitivity. Multivariate logistic regression analysis showed that T2 LAVmin, T3 LAVmin, T2 LAVprep, T3 LAVprep could independently predict the occurrence of cardiotoxicity. The remarkable thing is that LAVmin and LAVprep had a certain value in the diagnosis of cardiotoxicity after the second cycle of chemotherapy . After the third cycle of chemotherapy, the diagnostic efficacy is further improved , and it is higher than the traditional serological indicators such as cTnI and Pro-BNP. Therefore, the prediction of cardiotoxicity in patients based on the results of three-dimensional ultrasound had good clinical value and could be applied for evaluating the cardiotoxicity of MM patients in real time during chemotherapy.Three-dimensional ultrasound could evaluate cardiotoxicity by assessing changes of left atrial volume, and the detective results are highly correlated with CT and MRI evaluation results . Hatipogrization . The chan LAVmax . SimilarThere are some limitations in this study. First is the small sample size. Second, all the patients are recruited from one center. The third is a short duration of patients follow-up, and long-term follow-up is necessary to identify the significance of these early observations. Fourth, the time for changes in markers should be exactly identified. And more frequent blood sampling is needed. Therefore, conducting a multicenter, long-term, large-sample clinical study on cardiac toxicity to analyze the predicting values of left atrial volume changes in patients with multiple myeloma undergoing anthracycline chemotherapy is warranted for more precise detection of myocardial injury.The main aim of this research is to investigate the predictive value of echocardiographic parameters in the examination of anthracycline-related cardiac toxicity in multiple myeloma patients. This study has shown that the change of left atrial volume is a strong predictor of cardiotoxicity. Therefore, the assessment of left atrial volume changes might be a useful tool in the evaluation of patients with multiple myeloma undergoing anthracycline chemotherapy at risk of developing cardiotoxicity. This will help in the monitoring of these patients after they are treated with anthracycline chemotherapy and lead to the potential reduction in mortality and morbidity in these patients.


Aims: To determine the agreement between two-dimensional transthoracic echocardiography (2DTTE) and cardiovascular magnetic resonance (CMR) in left ventricular (LV) function  in chronic total occlusion (CTO) patients.Methods: Eighty-eight CTO patients were enrolled in this study. All patients underwent 2DTTE and CMR within 1 week. The correlation and agreement of LVEF, LVESV, and LVEDV as measured by 2DTTE and CMR were assessed using Pearson correlation, Kappa analysis, and Bland–Altman method.Results: The mean age of patients enrolled was 57 ± 10 years. There was a strong correlation  and a moderately strong agreement  between the two modalities in measurement of LV function. The agreement in patients with EF ≧50% was better than in those with an EF <50%. CTO patients without echocardiographic wall motion abnormality (WMA) had stronger intermodality correlations  and smaller biases in LV function measurement.Conclusions: The difference in measurement between 2DTTE and CMR should be noticed in CTO patients with EF <50% or abnormal ventricular motion. CMR should be considered in these conditions. For patients with coronary chronic total occlusion (CTO), left ventricular (LV) function assessment before revascularization is crucial for clinical decision-making and has reference value in evaluating the improvement of cardiac function status after revascularization , 2. LV fThe aim of this study was to determine the agreement between two-dimensional transthoracic echocardiography (2DTTE) and CMR in the assessment of LV function in CTO patients.N = 33) or incomplete CMR data (N = 1). The rest of the patients were referred to echocardiography examination and further excluded due to poor-quality images (N = 5), incomplete 2DTTE data (N = 4), or lack of 2DTTE images (N = 6), leaving 88 patients eligible for the study. All enrolled patients underwent both echocardiography and CMR imaging within the same week. Coronary artery interventions were not performed until both types of imaging were finished. The coronary occlusion duration was divided into three levels: certain, likely, and undetermined, as previously described  from May 2015 to June 2017, were enrolled in this study. As shown in Transthoracic echocardiography was assessed using standard clinical 2-dimensional imaging platforms: 56 patients with IE33 XMatrix  and 32 patients with Vivid 7 . All images were recorded and analyzed by an experienced echocardiologist, who was blinded to clinical data and CMR results.In each subject, assessments of LV function  were performed according to the recommendations of the American Society of Echocardiography  followinFor each patient, regional wall motion was assessed using a 17-segment LV model. The level of endocardial wall motion of each segment was scored according to previous guideline: score 1, normal or hyperkinetic; score 2, hypokinetic; score 3, akinetic; and score 4, dyskinetic  with a 32-element matrix coil. Images were obtained using steady-state and breath-hold cines in three long-axis planes and sequential short-axis slices extending from the mitral valve plane to just below the LV apex. End-diastolic and end-systolic volumes were obtained by manual delineation of the endocardial borders. Short-axis slices with ≧50% of the LV circumference surrounded by the myocardium were included in the process of volume calculation . The bast-test. Non-normally distributed ones were expressed as a median with interquartile range (IQR) and compared using the Mann–Whitney U-test. Categorical variables were expressed as percentages and compared using the chi-squared test. The intermodality correlation and agreement were tested using Pearson correlation, Kappa analysis, and Bland–Altman method, respectively. Bias and limits of agreement (LOA) were expressed as the mean and 95% confidence interval of the differences in normally distributed values and as median and 2.5th−97.5th percentiles of the differences in non-normally distributed values. All statistical tests were two-sided, and statistical significance was defined as P < 0.05.All analyses were performed using SPSS . For continuous variables, a Shapiro–Wilk test was used for normal distribution tests. Normally distributed values were expressed as means ± standard deviation (SD) and compared using Student's A total of 88 patients  with 90 CTO vessels were included in this study. Among them, 76 patients had presentation of angina (86.4%), 5 were diagnosed as non-ST-segment elevated myocardial infarction (NSTEMI) (5.7%), and 7 were asymptomatic (8.0%). Most of CTO lesions located in the right coronary artery (RCA) (44.4%), followed by left ascending branch (LAD) (40.0%) and left circumflex branch (LCX) (15.6%). The median interval between 2DTTE and CMR was 1 day. Further clinical data and LV functions are presented in P < 0.001 for all). . In detail, 78 patients had the same classification when measured by 2DTTE and CMR, and 67 of them (85.9%) had an EF≧50%. 2DTTE reclassified 10 of the total 88 patients (11.4%). Furthermore, in 9 of the 10 instances (90.0%) of reclassification, 2DTTE-derived EF values were overestimated (≥50%) than CMR-derived EF . , Table 2or all). , Table 2rived EF .Based on 2DTEE findings, non-WMA group had 48 patients, and WMA group included 40 patients with 43 segments of abnormal wall motion. Most of segmental WMAs occur in the inferior wall of LV, and the distribution of WMA was in consistence with dominant area of occluded coronary arteries . Among tCompared with the WMA group, the non-WMA group had significantly higher CMR-derived EF (59.0 ± 10.4 vs. 54.9 ± 16.1%)  and highIn this study, the results suggested that (a) there were strong correlations between 2DTTE and CMR for LV volume measurement in CTO patients; (b) for CTO patients with LVEF <50%, the strength of intermodality agreement might be lower and the EF was overestimated by 2DTTE; and (c) CTO patients with WMA had lower intermodality correlation and greater bias in LV evaluation.r = 0.71) was found to be lower than that in prior studies  when comparing the two modalities . AnotherFor patients in early stage of acute myocardial infarction, WMA can be observed due to temporary ventricular dysfunction. Among the five NSTEMI patients in this study, four of them had no transient or persistent WMA. Only one NSTEMI patient had WMA in inferolateral wall, which was more likely to be related to previous history of inferior myocardial infarction. Although the distribution of WMA was basically in consistence with occluded coronary arteries, no WMA was detected in the dominant area of CTO vessels in these five NSTEMI patients. The reason for the inconsistency was that timely revascularization avoids further ischemic impairment and ensured myocardial viability and normal ventricular motion.Besides, no significant difference was found in the history of myocardial infarction in comparison of patients with and without WMA. This suggests that WMA is not appropriate for diagnosis of myocardial infarction existence. In patients with cardiac microcirculation dysfunction or with equivocal evidence of cardiac ischemia, they may present with tiny or unrecognized infarction and undetectable WMA in echocardiography. In this condition, late gadolinium enhancement (LGE) performed by CMR can be better in the recognition of infarction lesions.In addition, lower strength of intermodality correlations for LV measurements and more significant bias in LVEF were observed in WMA group. The defect in the mechanism of echocardiography measurement was the main reason for this result. During the assessment and calculation of LV function, the interface between myocardium and ventricular cavity should be mapped at the end-diastole and end-systole stages in apical four and two-chamber views. The LV model is then made into a bullet shape and becomes the basis for measurements of volumetric values and EF calculation . A conciSeveral limitations of this study need to be addressed. First, this was a single center study with a small number of patients. Second, only CTO patients who underwent 2DTTE and CMR were enrolled. It may be better to expand this study to newly emerging modalities, including 3D echocardiography and cardiac computed tomography. Previous studies have confirmed that 3D echocardiography is superior to the 2D method when it comes to LV function assessment , especiaThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Beijing Anzhen Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study.XY and YHa collected the patient data. JL, LZ, and YW analyzed data and were major contributors in writing the manuscript. HZ, RH, YHe, and XS took the revision of the manuscript. All authors agree to be accountable for the content of the work.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.


Left ventricular dysfunction after surgical treatment of mitral stenosis isuncommon. We intend to determine the pattern of left ventricular remodeling,shortly after open mitral valve replacement for rheumatic mitral stenosis,with in-hospital postoperative outcomes and the determinants ofpostoperative worsening of left ventricular ejection fraction. From January 2008 to January 2015, 107 adult patients with rheumatic mitralstenosis were submitted to open mitral valve replacement. Their mean age was45±11 years and 93 (86.9%) were women. Left ventricular morphologyand function were studied longitudinally with echocardiography. The endpoint was postoperative worsening of left ventricular ejection fraction,defined by a decrease of 10% compared to preoperative basal assessment.Determinants of worsening left ventricular ejection fraction were determinedby multivariable logistic regression analysis.P=0.005; odds ratio [OR]=0.89) and smallerpreoperative mitral valve area  wereindependent predictors of left ventricular dysfunction. These patientspresented higher mortality and morbidity rates. The end point occurred in 18 patients (16.8%). We tested clinical andechocardiographic parameters to verify independent variables related to thedecrease in postoperative ejection fraction. Lower body weight( Left ventricular remodeling patterns differed among patients withpredominant rheumatic mitral stenosis undergoing open mitral valvereplacement. Lower preoperative body weight and mitral valve area wereindependent determinants of deteriorating ejection fraction with increasedend-systolic volumes, indicating that this specific problem may occur inanthropometric smaller patients with more extensive rheumatic disease. As opposed to mitral regurgitation, in which LVdysfunction may occur after surgery (as a compensatory mechanism of reduced end-diastolic volume),MS does not hold the same pathophysiological principle.The hallmark morphology of rheumatic mitral stenosis (MS) results from chronicendocardial insult in rheumatic fever carditis; commissural fusion, thickening, andnarrowing of the valve leaflets lead to obstruction of left ventricular (LV)filling. The exact mechanism remains unclear, but it isprobably multifactorial. Earlier studies found that these patients exhibit largerend-systolic volumes and lower ejection fractions (EF) with rigidity of the LVposterobasal wall at ventriculography; a diastolic dysfunction marked by altered ventricularcompliance and elevated end-diastolic pressure, with preserved EF and normal end-systolicvolume. Heart failurewith reduced or preserved EF in MS has been linked to chronic LV underfilling,endomyocardial fibrosis, subvalvular apparatus rigidity, and elevated rightventricular pressure,6-8.In MS, reduced stroke volume usually relates to reduced LV preload, rather thanventricular contractile impairment. However, some patients might present truesystolic dysfunction that is independent from LV preload that showed no improvementcompared to the control group, despite similar increases in mitral valve area (MVA).Although this is not a uniform finding, some authors have hypothesized that theincrease in the end-diastolic volume could worsen an underlyingdysfunction.Furthermore, LV remodeling after MS surgery is another critical issue, sinceknowledge of its pattern in terms of different preoperative echocardiographicparameters can offer a guide on the best timing for intervention. PreviousstudiesThe objectives of this study were to determine the pattern of LV remodeling, shortlyafter open mitral valve replacement for rheumatic MS, with in-hospital postoperativeoutcomes and the determinants of postoperative worsening of LVEF.From January 2008 to January 2015, 107 adult patients with pure rheumatic MS ormixed lesions with predominant MS were submitted to primary open mitral valvereplacements, associated or not with tricuspid valve repairs and/or Cox-mazeprocedures. Exclusion criteria included more than moderate mitral regurgitation,aortic valve pathology, previous cardiac surgery, patients submitted to mitralvalve repair, and those with incomplete follow-up.Data were retrieved in part from the prospective cardiovascular surgery registryand in part from each electronic patient’s medical record. All echocardiographicanalysis was performed in our institution by a team of qualified physiciansfollowing strict standardized protocols. Routine periodic interobservervariability is tested in our laboratory. Echocardiographic data were obtainedfrom the echocardiography laboratory records. These data were approved by theInstitutional Review Board , whichapproved their use for research purposes with patient consent waived.Operations were performed with normothermic cardiopulmonary bypass andhypothermic antegrade and retrograde blood cardioplegia for myocardialprotection. Mitral valve replacement was performed with partial preservation ofthe subvalvular apparatus. The anterior leaflet was systematically resected. Theposterior leaflet was preserved entirely or partially resected, in order avoidinterference with the movement of the prosthesis leaflets and with LV filling.Secondary chordae were resected where extensive fibrotic tissue foreshortenedthe subvalvular apparatus, in addition to papillary muscle splitting to allowbetter ventricular filling. All calcified leaflet tissue was routinely removed.There were no patients in this series with mitral annular calcification in needof decalcification and reconstruction of the posterior atrioventriculargroove.All patients were submitted to a comprehensive two-dimensional and Dopplerechocardiogram  using 2/4 MHz transducer and second harmonic imaging, beforeand after any cardiothoracic surgical procedure in our unit. For the purpose ofthis research, the closest examinations performed before and after the surgerywere reviewed. All postoperative examinations were completed prior to patientdischarge.LVEF was determined by the Simpson method. Left atrial volume (LAV) wascalculated by the modified Simpson method and indexed to body surface areas. LAVwas measured in the frame just before mitral valve opening, excluding the leftatrial appendage and pulmonary veins.. Mean mitral valve diastolic gradients were measured bypulsed-wave Doppler. After valve replacement, patients were additionallyevaluated for PHT and Doppler velocity index.MVA was measured by the planimetry method, using a parasternal short-axis viewand pressure half-time (PHT), complying with the American Society ofEchocardiography Guidelines, which establishes a standard deviation offive absolute points for the mean normal values of LVEF, for both genders. Thatdifference of > 10% was validated because it is greater than theinterobserver accepted assessment error that may occur in echocardiography.LV remodeling was studied through changes in LV dimensions, volumes, and functionshortly after mitral valve replacement. For the purpose of this study, worseningof LV function was defined by a decrease in the LVEF of 10% or more betweenpreoperative and postoperative echocardiographies. These criteria were based onthe latest guidelines issued by the American Society of Echocardiography and theEuropean Association of Cardiovascular ImagingThe outcomes assessed included intraoperative support , as well as postoperative in-hospital mortality andmorbidity rates .All statistical analyses were performed using IBM Corp. Released 2016, IBM SPSSStatistics for Windows, Version 24.0, Armonk, NY: IBM Corp. Categoricalvariables are summarized as frequencies and percentages. The distributionpatterns of variables were determined by the Kolmogorov-Smirnov test. Continuousvariables are summarized as means and standard deviation when normallydistributed or as medians with interquartile range when the data is skewed.2 or Fisher’s exact test (withless than five observations). Continuous outcomes were compared either byparametric tests (Student’s t-test) when variables had normaldistribution, or by non-parametric tests (Mann-Whitney and Wilcoxon) whenvariable distribution was skewed. To compare temporal pattern of postoperativeechocardiographic indices of dimensions and function across time, all repeatedcontinuous values were analyzed longitudinally using repeated measures analysesof variance. Clinical and echocardiographic variables related to the developmentof postoperative worsening of LV function were determined by multivariablelogistic regression. First, we determined factors associated with postoperativeworsening of LV function using a univariable model. Variable selection, with aP-value criterion of 0.2 for retention of variables in themodel, was followed by variable storage using automated forward selection andbackward elimination. Receiver operating characteristic curves were obtained andthe area under the curve was determined. A P-value of 0.05 wasconsidered statistically significant.Categorical outcomes were compared using either χP<0.01), that determined lower body mass index(P<0.01) and body surface area(P<0.01).Overall, there was a marked predominance of women , and the mean age was45±11 years (range from 22 to 71 years). More than half of the population hadpreoperative atrial fibrillation and they were in New York Heart Association (NYHA)functional class III or IV . Mitralvs.72.2% of worsening EF group; P=0.4), its sizing , presence ofconcomitant procedures - Maze procedure and/or tricuspid repair  -, and duration ofcardiopulmonary bypass time  and aortic cross-clamping time.Intraoperative variables did not differ among study groups. Those include the type ofprosthesis used (bioprosthesis in 59.1% of preserved EF group P<0.01), its means were in the normal range.Worsening of LVEF > 10% occurred in 18 patients (16.8%) and only six patients(5.6%) presented EF < 50%.Postoperatively , there wF=0.04; P=0.83)and volumes  increasedsimilarly. The increase in the end-systolic volume , as shown in F=43.1;P<0.01) was far greater in the group that presentedworsening of EF. Moreover, the mitral valve orifice area . Both groupspresented similar decreases in LAV  and proportional improvements in pulmonary arterysystolic pressures .When the groups were compared ,LV end-ice area  was smalP=0.005; odds ratio [OR]=0.89) and MVA were identified as independent predictorsof worsening of LVEF. Moderate mitral regurgitation was not associated withworsening of postoperative EF.Body weight (P<0.01).A receiver operating characteristic curve was then obtained for the MVA byplanimetry. Regarding the non-indexed MVA, the optimal cutoff for prognosticvalue was determined by the model as 0.8 ,with an overall area under the curve of 0.752  and about half withpreoperative atrial fibrillation. Patients submitted to mitral valve repair wereexcluded since this could be a confounder when analyzing LV remodeling patterns., but underlyingsystolic dysfunction could be unmasked after surgery. LVEF has limitations fordefining the degree of systolic ventricular dysfunction. Echocardiographic assessment with speckletracking echocardiography has demonstrated that longitudinal and circumferentialstrain rates are globally diminished in MS patients, even with preserved EF.The pattern of ventricular remodeling in patients presenting with worsening of LVEFwas associated with greater ventricular dilatation. Moreover, they also had smallerpreoperative mitral valve orifice areas, indicating more severe MS at presentation.This finding might be related to poor adaptation by the left ventricle to a subtleincrease in end-diastolic volumes. Diastolic dysfunction is usually the explanationfor that ,.Moreover, a positive correlation was found between MVA and impaired longitudinalstrain rates. However, theseresults are not consistent in patients with mild to moderate MS isnecessary as an indication for surgery. It is also considered reasonable as anindication for percutaneous balloon valvuloplasty (rather than surgery) aRecommendation Class IIa in asymptomatic patients with very severe MS  and favorablemorphology, in the absence of contraindications. This recommendation stresses theincremental risk of very severe MS (MVA < 1.0 cm2) over severe stenosis (MVA < 1.5 cm2), even in stage C patients. The 2017European Society of Cardiology/European Association for Cardio-Thoracic SurgeryGuidelines on valvulardisease recommend as an indication that intervention in asymptomatic patients beperformed only percutaneously, with high thromboembolic risk and/or high risk ofhemodynamic decompensation, at the same recommendation level as the Americanguidelines. The Brazilian Society of Cardiology Guidelines recommend intervention as ClassIIa in asymptomatic patients, only in the presence of pulmonary hypertension and/ornew-onset atrial fibrillation, if not suitable for percutaneous balloonvalvuloplasty. Our data supports this indication for surgery based on symptoms aloneor with complicating factors  that may be misleading, particularly when MVA < 1.0cm2.The 2014 American Heart Association/American College of CardiologyGuidelines2 presented good sensitivity (88.2%)and low specificity (54.4%), raising concerns about very severe MS and postoperativesubclinical ventricular dysfunction.Our data showed that worsening of LVEF > 10% is associated with poorer in-hospitaloutcomes. Similarly, proper assessment of LV systolic and diastolic function isimportant for determining surgical risk and prognosis. Early intervention seemsreasonable for this patient subset. In our study, MVA of 0.80 cmThis is a retrospective patient cohort study, with its inherent limitations. Thelow number of events curtailed a more appropriate analysis of outcomes withmultivariable logistic regression, particularly those that achieve worseningLVEF (N=19). However, a fair number of rheumatic MS patients were included. Theimportance of this study lies in the recognition that there is a subset ofpatients who develop clinically relevant LV adverse remodeling. Long-termclinical and echocardiographic data would be extremely important forunderstanding whether ventricular remodeling pattern persists over time,together with its impact on survival.LV remodeling patterns differed among patients with predominant rheumatic MSundergoing open mitral valve replacement. Lower preoperative body weight and MVAwere independent determinants of deteriorating EF with increased end-systolicvolumes, indicating that this specific problem may occur in anthropometric smallerpatients with more extensive rheumatic disease.


The left ventricle (LV) constantly changes its shape and function as a response to pathological conditions, and this process is known as remodeling. In the presence of aortic stenosis (AS), the degenerative process is not limited to the aortic valve but also involves the remodeling of LV. Statistical shape analysis (SSA) offers a powerful tool for the visualization and quantification of the geometrical and functional patterns of any anatomic changes. In this paper, a SSA method was developed to determine shape descriptors of the LV under different degrees of AS and thus to shed light on the mechanistic link between shape and function. A total of  Aortic stenosis (AS) is a common cardiovascular disease in the developed countries. This type of valvulopathy manifest in 5% of the general population at age of 65 years with increasing prevalence in elderly . Specifin = 30 patients referred for aortic size evaluation were included as a control group because of no-sign of AS and/or regurgitation and preserved LV function. Patient exclusion criteria were uncontrolled history of hypertension, connective tissue disorders, medication or history of coronary artery disease or myocardial infarction. The remaining n = 56 patients were stratified into two groups based on the severity of AS  according to clinical guidelines on the management of aortic valve diseases of the European Society of Cardiology [A total of rdiology . To straFor each patient, ECG-gated cardiac CT images were reconstructed, following a structured reverse engineering approach ,19, to iFor each patients, we calculated the end-systolic volume (ESV), the end-diastolic volume (EDV) and the stroke volume (SV). The cardiac output (CO) and the left ventricular mass index (LVMI) were also calculated using clinical demographic data.The SSA was performed using a custom algorithm developed in the mathematical language program MATLAB  as described by Consentino et al. . To captAll LV surfaces were initially aligned to a reference shape that was extrapolated from the patient study group with moderate stenosis as this represents the average shape of our patient population. However, the alignment of LV surfaces to the reference shape can lead to an initial template shape that is quite biased with respect to the initial reference shape. Thus, a new set of shape transformations were developed from the initial template shape to each rigidly aligned shape. The rigid alignment was therefore repeated, using the mean LV surfaces as the reference shape. To reduce bias, the previous steps of rigid alignment, followed by shape transformation and, again, rigid alignment, were repeated a number of times upon the average shape did not change. The so-obtained aligned LV models were therefore used as input for the PCA. The latter is currently one of the most widely used dimension reduction procedures. Using orthogonal transformations, PCA performs a projection of data onto a linear space of maximum variation directions, known as “shape mode” or “mode”. Shape modes are specific aspects of the anatomical LV variation induced by the degree of AS, and help to understand the morphological features that cannot be described by image-based measurements . After PTwo PCA models for each patient group were considered, the first using the LV surfaces reconstructed at ES and the second using the LV surfaces at ED. After PCA, Pearson correlation was used to explore the relationships between shape modes and functional variables of LV performance. A logistic regression model was also developed to determine which modes is most associated with the occurrence of adverse events (non-complicated versus complicated patients). The weight of shape modes  were used as a predictor for the classification of the patient class. ROC curves were plotted to compute the area under the ROC curve as an index of the predictive value of the regression model. This model was then compared to a baseline model, using clinical demographic data as predictor of adverse events  induced by the diseased aortic valve. Statistics was performed using the SPSS software  assuming all probability values considered significant at 0.05 threshold.For the patient study groups with moderate and severe AS, p = 0.012, R = 0.820) while Mode 8 was negatively correlated with the diastolic pressure . For moderate stenosis, Mode 5 was positively correlated with the CO measured by echocardiography .At Pearson’s correlation, we observed a statistically significant positive relationship between the Mode 1 and the ESV  were computed for each model, see In order to develop a prognostic model to estimate the probability of repair of diseased aortic valve, a logistic regression based on shape modes retained upon 90% of shape variability was performed. Specifically, the shape modes computed at ES and ED were combined together into one vector. Then, this model was compared to a baseline model considering clinical demographic data as predictors of AS repair. The follow-up period was 3.5 years for control group and 4.6 years for the patient study group with aortic stenosis. The coefficients  segmentation of LV wall, (2) PCA of the aligned LV models with respect to a template, (3) detailed quantification of the association between functional parameters and LV shape modes using Pearson’s correlation and logistic regression. We speculated that specific shape features characterize the LV remodeling induced by different degrees of AS and may be predictors of adverse events . Findings supported this hypothesis, with extracted shape modes statistically associated with the disease status. Sphericity represented the main variation in the LV shape and had a strong correlation with both ESV and EDV, thereby suggesting LV impairment with severe AS. Moreover, the PCA-related model built with shape modes performed better than traditional clinical metrics of remodeling based on demographic data and functional parameters . This SSA approach can be therefore adopted as a clinical tool to extract 3D shape biomarkers characterizing the patterns of LV remodeling induced by the stenotic aortic valve. We described how SSA has the potential to discover previously unknown 3D shape biomarkers in a challenging patient population and to develop predictive model integrating diagnostic imaging and mathematical modeling to improve decision making. Using longitudinal imaging data, the SSA can be used to track individual patients over time and identify LV geometries who are likely evolving towards adverse outcomes and thus deserve a more aggressive management. However, further studies are needed to confirm the prognostic potential of novel 3D shape biomarkers of LV wall in the setting of AS.In failing heart, ventricular size and shape are the most common geometric aspects of the LV wall. Quantitative post-mortem anatomic observations revealed a more spherical shape of dilated hearts after myocardial infarction . This clFor this reason, SSAs have demonstrated the potential to reveal new measures of geometry and function as they integrate all anatomical shape information intuitively as a visual and numerical mean shape and its variation in 3D . Such atThe study has the disadvantages of a retrospective design, with limited and an uneven number of patients in each subgroup. Indeed, the complicated study group included patient with moderate valve stenosis who underwent surgery because of concomitant cardiac or vascular complications. This has likely affected the statistical analysis but aortic stenosis is often associated to detrimental effects on LV function and a loss of arterial elasticity. Thus, aortic stenosis cannot be considered as an isolated disease. There was also not any significance on the left ventricular hypertrophy  in the patient group with severe aortic stenosis as compared to that of patient with moderate stenosis and controls. In the logistic regression model, gender differences were included because of the general consensus on the high risk of cardiovascular events in the male versus female population, and this has likely influenced model output. Most importantly, the segmentation of LV geometry did not include the stenotic aortic valve as this was not seen at CT scan. This is in part justified by the fact that the adaptation of the LV wall to the disease progression is mainly accompanied by changes in ventricular size and shape. Findings presented in this study are meanly meant to demonstrate the potential of the proposed SSA approach by studying the association of complex 3D shape features with functional echocardiographic parameters. In patients with AS, our approach applied to a larger and heterogonous patient cohort could help to understand the efficacy and predictive capability of LV shape modes for early diagnosis of the valvulopathy.In this study, the complex shape features of the left heart chamber were extracted by SSA and then correlated to clinical and functional data of patients with different degrees of AS. This was performed to shed light on shape and function as well as improve patient risk prediction using a detailed 3D shape analysis at minimal human intervention.