To improve the echocardiographic assessment of heart failure in patients with atrial fibrillation (AF) by comparing conventional averaging of consecutive beats with an index-beat approach, whereby measurements are taken after two cycles with similar R-R interval.Transthoracic echocardiography was performed using a standardised and blinded protocol in patients enrolled in the RATE-AF  randomised trial. We compared reproducibility of the index-beat and conventional consecutive-beat methods to calculate left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and E/e’ , and assessed intraoperator/interoperator variability, time efficiency and validity against natriuretic peptides.160 patients were included, 46% of whom were women, with a median age of 75 years (IQR 69–82) and a median heart rate of 100 beats per minute (IQR 86–112). The index-beat had the lowest within-beat coefficient of variation for LVEF , GLS  and E/e’ . Intraoperator (n=50) and interoperator (n=18) reproducibility were both superior for index-beats and this method was quicker to perform (p<0.001): 35.4 s to measure E/e’ (95% CI 33.1 to 37.8) compared with 44.7 s for 5-beat (95% CI 41.8 to 47.5) and 98.1 s for 10-beat (95% CI 91.7 to 104.4) analyses. Using a single index-beat did not compromise the association of LVEF, GLS or E/e’ with natriuretic peptide levels.Compared with averaging of multiple beats in patients with AF, the index-beat approach improves reproducibility and saves time without a negative impact on validity, potentially improving the diagnosis and classification of heart failure in patients with AF. The prevalence of atrial fibrillation (AF) is climbing,The aim of this study was to systematically compare the reproducibility and efficiency of a more physiological approach to improve the assessment of heart failure in patients with AF. The index-beat method takes into account time-dependent processes involved in contractility and relaxation.Baseline echocardiograms were evaluated for all participants enrolled in the RATE-AF  randomised trial after obtaining written informed consent (NCT02391337). The trial received oversight from a trial steering committee and data monitoring committee with independent chairs. The rationale and methods for the RATE-AF trial have previously been published.AF was confirmed on 12-lead ECG. All patients then underwent transthoracic echocardiography using Philips EPIQ 7 and X5-1 transducer, by an experienced echocardiographer accredited with the British Society of Echocardiography. Patients were positioned in left lateral decubitus position and images were acquired during quiet respiration according to an echocardiography protocol ratified prior to the trial commencing.A minimum of 30-beat loops were obtained of the apical two-chamber, three-chamber and four-chamber views. All images were optimised to maximise frame rate while ensuring all left ventricular segments were visible. A minimum of 30 traces of tissue Doppler imaging (TDI)-derived lateral and septal e’ were obtained and mitral inflow using pulse wave Doppler acquired at a sweep speed of 50 mm/s. The recorded images were given a unique identification number and all patient-identifiable features  were removed, blinding the operator to patient, trial and clinical details.All measurements were analysed offline by the same operator a minimum of 3 months after the scan date. To minimise selection bias, there were no predefined exclusions made on the quality of imaging; however, if image quality was insufficient to accurately obtain measurements, these images were excluded from analysis. All analyses were performed on Philips Q-Station . For LVEF, Simpson’s biplane LVEF was measured from the apical four-chamber and two-chamber views. Longitudinal strain was taken from the apical two-chamber, three-chamber and four-chamber views and then averaged to generate overall global longitudinal strain (GLS). The mean frame rate for GLS acquisition was 57 Hertz (SD 7.0). For E/e’, mitral valve peak E velocity was measured and then divided by the TDI-derived e’ .The index-beat was identified as the cardiac cycle which followed a preceding and pre-preceding R-R interval of similar duration  with a single index-beat and an average of 3, 5 and 10 beats.A second accredited operator obtained images in 18 randomly selected patients to measure GLS and E/e’ using a single index-beat and average of 3, 5 and 10 beats. The operator was blinded to the previously recorded measurements as well as all clinical details of each echocardiogram. The time taken to select and measure E/e’ using a single index-beat and guideline-recommended 5 and 10 consecutive beats was measured, with time commencing from the first visualisation of Doppler images.All patients had N-terminal pro-B-type natriuretic peptide (NT-proBNP) measured on the same day as their echocardiogram using an Abbott Alinity platform. This was correlated with the parameters LVEF Simpson’s biplane, GLS and E/e’.A patient and public involvement team were involved in the design and conduct of this study and assisted with the plain English summary.2)−1×100; 95% CIs were calculated for each CV. For intraoperator and interoperator reproducibility, Bland and Altman analysis was used to obtain the mean bias and limits of agreement, and the ICC with 95% CI was calculated at the patient level for each measurement method using a multilevel mixed effects linear regression model (adjusting for the random effects of the patient and the time the measurement was taken). The statistical comparison of time taken was performed using a two-tailed t-test accounting for unequal variance. The association with NT-proBNP was compared using Spearman’s r and univariate linear regression analysis. The difference in correlation coefficient between measuring on an index-beat and averaging 3, 5 and 10 consecutive beats was calculated using the method of Meng et al.Summary results are presented as percentage, mean with SD, or median with IQR (displayed as 25th–75th quartiles). All echocardiographic measurements were transformed to their natural log value. A multilevel mixed effects linear regression model (adjusting for the random effects of the patient) was used to calculate the intraclass correlation coefficient (ICC) and derive the SD (σ), with 95% CI for the within-beat variability. Post-hoc analysis indicated >90% assurance that the sample size was sufficient for ICC comparison.One hundred and sixty patients were included, with a median age of 75 years (IQR 69–82), heart rate of 100 beats per minute at time of acquisition (86–112) and blood pressure of 134/84 mm Hg (123/76–148/93) see . The med10.1136/heartjnl-2020-318557.supp1Supplementary dataThe index-beat approach had less variability compared with conventional consecutive beat averaging for all comparisons of CV for LVEF, GLS and E/e’ . In all For LVEF, the index-beat approach had the smallest CV of 32% (95% CI 31 to 34) and strongest ICC of 0.94 (0.93 to 0.96), compared with 54% (52 to 57) and 0.71 (0.64 to 0.77) for 3 consecutive beats, 51% (50 to 53) and 0.76 (0.71 to 0.81) for 5 consecutive beats, and 53% (52 to 54) and 0.74 (0.69 to 0.79) for 10 consecutive beats. The mean RR1 of the index-beat  was 552 ms and the mean RR2  was 555 ms, with a mean RR1 to RR2 ratio of 1.00.For GLS, the index-beat approach had the smallest CV of 26% (95% CI 25 to 27) and strongest ICC of 0.88 (0.85 to 0.91), compared with 44% (42 to 46) and 0.81 (0.76 to 0.85) for 3 consecutive beats, 43% (42 to 44) and 0.82 (0.77 to 0.85) for 5 consecutive beats, and 42% (41 to 43) and 0.80 (0.75 to 0.84) for 10 consecutive beats. The mean RR1 of the index-beat was 568 ms and the mean RR2 was 570 ms, with a mean RR1 to RR2 ratio of 1.09.For E/e’, the index-beat approach had the smallest CV of 25% (95% CI 24 to 26) and strongest ICC of 0.96 (0.95 to 0.97), compared with 40% (37 to 41) and 0.81 (0.76 to 0.85) for the average of 3 beats, 41% (40 to 43) and 0.77 (0.72 to 0.81) for the average of 5 beats, and 41% (41 to 42) and 0.78 (0.73 to 0.81) for the average of 10 beats. The mean RR1 of the index-beat was 653 ms and the mean RR2 was 655 ms, with a mean RR1 to RR2 ratio of 1.00.Intraoperator reproducibility of the index-beat method compared with consecutive beat averaging was assessed in 50 patients for E/e’ and GLS , compared with averaging 5 consecutive beats  or 10 consecutive beats  . Using tDespite only using a single index-beat, there was no evidence that this impacted on the validity; there were no significant differences in the correlation of NT-proBNP with echocardiographic variables when comparing index-beats with conventional averaging . For exaThis study has demonstrated that the index-beat method produces more reproducible quantification of systolic and diastolic left ventricular function in patients with AF than conventional averaging of consecutive beats, while saving time and without compromising validity. The within-beat coefficient of variability and intraobserver/interobserver reproducibility were all favourable using the index-beat approach to imaging in patients who have a variable stroke volume and filling time. Using the index-beat method routinely in clinical practice has the potential to improve workflow and productivity, enhance the reliability of echocardiography, and provide more confidence in the diagnosis and classification of heart failure in patients with AF.Heart failure is common in patients with AF, and accurate assessment of systolic and diastolic left ventricular function is essential for patient management.It is important to note the very high levels of variation we demonstrate using the guideline-recommended 10 consecutive-beat analysis; the CV of 41% for E/e’ should be considered unacceptable, highlighting the limitations of current practice in patients with AF. The influence of the R-R interval on contractility is believed to be caused by preload and uptake of calcium during the relaxation phase. The longer the R-R interval, the more time for calcium uptake and the greater the amount released in response to the sequential action potential, triggering a greater force of contraction.Intraoperator reproducibility for both GLS and E/e’ was shown to be highest when measuring on a single index-beat. Previous studies assessing strain rate have found a strong correlation between the index- beat and averages of 10 and 15 beats with high levels of agreement.A major concern with nearly all previous studies is the preselection of patients with ‘good echocardiography windows’.In a blinded analysis without preselection for image quality, assessing left ventricular function using the index-beat method provides a more reproducible and quicker method of assessing heart function in patients with AF. Pending independent validation, our results suggest that echocardiography departments should change to the index-beat method to diagnose and characterise heart failure in patients with AF.Accurate assessment of ventricular function is essential to diagnose the type of heart failure in patients with atrial fibrillation (AF) and guide treatment strategies.However, measuring ventricular function in patients with AF is challenging due to the irregular cardiac cycle length.The index-beat approach, whereby measurements of ventricular function are taken after two cycles with a similar R-R interval, was compared with conventional averaging of consecutive beats.We demonstrated that the index-beat approach was more reproducible, more time-efficient and did not compromise clinical validity against natriuretic peptide levels.Pending external validation, use of the index-beat in clinical practice could improve the assessment of ventricular function, leading to more precise treatment strategies for patients with AF and the potential for fewer hospital admissions and better patient quality of life.


The purpose of this study is to dynamically monitor the myocardial structure and function changes in diabetic mini-pigs by 1.5 T cardiac magnetic resonance.Three male mini-pigs underwent cardiac magnet resonance (CMR) imaging, and histologic examination. T1-mapping was acquired at basal, mid and apical segments. CMR feature-tracking (CMR-FT) is used to quantify left ventricle global longitudinal (LVGLS), circumferential (LVGCS) and radial strain (LVGRS). Epicardial adipose tissue (EAT) was evaluated using a commercially available software.2, p < 0.001; Native T1: 1005.5  vs. 1028.7  ms, p = 0.041; EAT: 16.1  vs. 24.6  mL, p = 0.020; ECV: 21.4  vs. 28.9  %, p = 0.011; LVGLS: − 22.8  vs. − 17.4 %, p = 0.008). The diffuse myocardial interstitial fibrosis was found in histology samples.Left ventricular mass (LVM), myocardial native T1 value, extracellular volume (ECV) value and EAT were increased gradually after 6 months of modeling, while LVGLS decreased gradually after 6 months of modeling  vs. 42.7  g/mThe progressive impairments in LV structure and myocardial deformation occurs in diabetic mini-pigs. T1 mapping and CMR-FT technology are promising to monitor abnormal changes of diabetic myocardium in the early stage of diabetic cardiomyopathy. In 2010, the prevalence of diabetes among adults (20–79 years old) was 6.4%, reaching 285 million people, but the prevalence rate will increase to 7.7%, and the number will reach 439 million in 2030 [Cardiac magnetic resonance (CMR) cine imaging is the gold standard for evaluating myocardial structure and function in many cardiac diseases. In recent years, as a new and sensitive technique of measuring myocardial deformation and function, CMR tissue tracking (CMR-FT) method based on the cine images has been widely used in myocardial strain analysis of different types of cardiomyopathy , 7, and So far, the researches on diabetic cardiomyopathy mainly focus on patients with type 2 diabetes . HoweverAll animal experiments were approved by Institutional Animal Care and Use Committee, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China and were executed conforming to the “Guide for the Care and Use of Laboratory Animals” and in compliance with the ARRIVE guidelines. Three male mini-pigs, aged 5–6 months, were provided by the Laboratory Animal Center of Tongji Medical College. Type 1.5 DM animal models were induced by intravenous injection of streptozotocin at a dose of 150 mg/kg . FastingThe mini-pigs were anesthetized through intravenous injection of pentobarbital sodium (0.1 mg/kg min). All three pigs have a pre-DM scan in our study, and all pigs have a post-DM scan at 1.5, 3, 4.5 and 6 months. Hematocrit level (HCT) was measured by collecting blood from ear vein before MR scanning was performed.2; and matrix, 256 × 205. T1 mapping technique was performed at the basal, mid and apical slices of the left ventricular short axis before and 15 min after the administration of gadolinium-diethylenetriamine pentaacetic acid (DTPA)  using a prototype-modifed Look-Locker inversion recovery (MOLLI) sequence. The following parameters were used: repetition time, 3.89 ms; echo time, 1.12 ms; flip angle, 35°; slice thickness, 8 mm; field of view, 360 × 270 mm2; matrix, 256 × 192; iPAT factor, 2; and acquisition scheme, 5b(3b)3b. The ECV mapping image is generated automatically by inputting the value of HCT through a prototype inline processing function from Siemens, based on native and post-contrast T1 mapping at the same slice and the subject-specific HCT value.All three pigs underwent a standard CMR examination with a 1.5 T scanner . A balanced steady-state free procession (b-SSFP) sequence was performed to acquire left ventricular long-axis and short-axis (coverage from the base to the apex segment) cines. The parameters included: repetition time, 2.93 ms; echo time, 1.16 ms; flip angle, 80°; slice thickness, 6 mm; field of view, 340 × 255 mmArgus software  was used to analyze cardiac structure and function. The basic parameters of cardiac function, including left ventricular end-diastolic volume (LVEDV); Left ventricular end-systolic volume (LVESV);Left ventricular ejection fraction (LVEF); Left ventricular mass (LVM). In order to avoid the influence of partial volume effect, the native T1 and ECV values were measured by manually sketching the region of interest (ROI) in the interventricular septum myocardium of the left ventricular basal, middle and apical segments Fig. . EAT meaMyocardial systolic strains were analyzed and processed using commercial cardiovascular postprocessing software  to obtain global measurements of LV strain. All the continuous short axis films and two-,three-, and four-chamber long-axis images were imported into Medis 3.0 software offline. At the end of diastole, the left ventricular endocardial and epicardial contours were manually delineated on the short axis and the long axis respectively. The trabecular and papillary muscles were included within the heart cavity . Continuous variable are presented as median and range (lowest and highest). One way analysis of variance (ANOVA) was used to compare baseline and the value of the relevant index at 6 months. For all comparisons, statistical significance was considered at a The LV strain of three mini-pigs were analyzed independently by two experienced observers. One observer made another analysis after 14 days. The repeatability of parameters within and between observers were calculated respectively. By calculating the inter class correlation coefficient (ICC), the repeatability of multiple measurements was analyzed.2, p < 0.001; LV remodeling index: 0.8  vs. 1.7 , p < 0.001; Native T1: 1005.5  vs. 1028.7  ms, p = 0.041; EAT: 16.1  vs. 24.6  mL, p = 0.020; ECV: 21.4  vs. 28.9  %, p = 0.011; LVGLS: − 22.8  vs. − 17.4 %, p = 0.008)  values of nativeT1, ECV, EAT, LVGRS, LVGCS and LVGLS measured by the same physician were 0.974, 0.957, 0.945, 0.985, 0.869 and 0.934 respectively. The ICC values of nativeT1, ECV, EAT, LVGRS, LVGCS and LVGLS were 0.969, 0.973, 0.948, 0.981, 0.893 and 0.926 respectively, measured by two different physicians.This animal model simulates the type 1.5 DM model of human disease, the advantages of this model not only avoid the effect of various confounding factors in patients on diabetic cardiomyopathy, such as age, the course of the disease, and coexisting diseases, but also obtain the imaging indicators of myocardial fibrosis by non-invasive imaging method and compare them with myocardial histological alterations to insight into the pathogenesis of DCM. The main findings of this study were that (1) the increases of myocardial T1 value, ECV and LVM and the decrease of left ventricular GLS were found at the 3rd months of modeling, and (2) EAT abnormalities were observed at the 6th months of modeling compared to the base line.T1 mapping can early monitor myocardial focal and diffuse fibrosis by quantifying myocardial T1 and extracellular volume values, and it has been confirmed in previous histological studies . Our resIn this study, it was found that the LV remodeling index (LV mass/volume ratio) was increased after the modeling of 4.5 months. We also found that LVM was increased after the modeling of 1.5 months. Similar results were reported by Sorensen et al. , 19 in aEAT comprises adipocytes, stromo-vascular cells, neurons, and immune cells , 24, whiIn this study, three limitations should be considered. First, our animal sample size was small, which greatly reduced the power of the study and did not allow us to draw generalized conclusions. We will continue to expand our sample size in our future studies on this topic. Second, our study was unable to carry out serial histological validation evaluation at various timepoints in type 1.5 DM animal models because pigs are large animals and limited by many experimental conditions. Third, impaired myocardial perfusion is one of the key characteristics of diabetic cardiomyopathy. However, due to technical reasons, we failed to do stress myocardial perfusion after many attempts. In the next experiment, we'll explore this myocardial perfusion imaging technique.In summary, our study suggests that increases in LVM, myocardial native T1, ECV, and EAT can be detected prior to a decline in left ventricular systolic function as diabetes progresses in diabetic mini-pigs. LVGLS is impaired gradually with the prolonged course of diabetes. Whether LV systolic dysfunction can be ascribed to the true effect of DM or to a confounding effect of DM and EAT still requires further study. T1 mapping and myocardial strain analysis are promising method in detecting subtle myocardial dysfunction in the early stages of DM.


Paediatric cardiomyopathies are a heterogenous group of rare disorders, characterised by mechanical and electrical abnormalities of the heart muscle. The overall annual incidence of childhood cardiomyopathies is estimated at about 1 per 100,000 children and is significantly higher during the first 2 years of life. Dilated cardiomyopathies account for approximately half of the cases. Hypertrophic cardiomyopathies form the second largest group, followed by the less common left ventricular non-compaction and restrictive phenotypes. Infectious, metabolic, genetic, and syndromic conditions account for the majority of cases. Congestive heart failure is the typical manifestation in children with dilated cardiomyopathy, whereas presenting symptoms are more variable in other phenotypes. The natural history is largely influenced by the type of cardiomyopathy and its underlying aetiology. Results from a national population-based study revealed 10-year transplant-free survival rates of 80, 62, and 48% for hypertrophic, dilated and left ventricular non-compaction cardiomyopathies, respectively. Long-term survival rates of children with a restrictive phenotype have largely been obscured by early listing for heart transplantation. In general, the majority of adverse events, including death and heart transplantation, occur during the first 2 years after the initial presentation. This review provides an overview of childhood cardiomyopathies with a focus on epidemiology, natural history, and outcomes. Paediatric cardiomyopathies form an uncommon and heterogenous group of disorders, which are characterised by structural, mechanical, and electrical abnormalities of the heart muscle , 2. AetiDilated cardiomyopathy (DCM) is characterised by left ventricular dilation and systolic dysfunction. Important aetiologies in childhood include infections, toxic causes (including chemotherapy), genetic mutations, and other causes such as inborn errors of metabolism and neuromuscular disorders . Recent DCM is the most common type of childhood cardiomyopathy. It comprised about half of all cases in the Paediatric Cardiomyopathy Registry (PCMR), a large multicentre North American study, as well as in the National Australian Childhood Cardiomyopathy Study (NACCS), a population-based cohort study which included children younger than 10 years of age at diagnosis. The overall incidence was 0.58–0.73 per 100,000 children and varied significantly by age see . In bothThe majority of children with DCM, particularly infants, present with varying severity of congestive cardiac failure, with symptoms ranging from feeding difficulties to cardiovascular collapse, and rarely sudden death. Older children with a positive family history and those with neuromuscular disorders or inborn errors of metabolism may be diagnosed as part of routine screening, prior to symptom onset. Lymphocytic myocarditis has a phenotype that may be indistinguishable from idiopathic DCM. A history of a prior viral illness is not always present and may be misleading . Data frOutcomes for children with DCM are highly variable, ranging from complete recovery to death or requirement for transplantation. Beyond infancy, DCM is the most common indication for heart transplantation in children . Data frz-score and failure to improve fractional shortening z-score during follow-up  and posterior wall thinning were identified as risk factors for sudden death  in DCM from the PCMR and found a 5-year incidence of 3%. Younger age at diagnosis (<14.3 y), systolic LV dilation  is a condition characterised by left or biventricular hypertrophy in the absence of structural heart disease or increased ventricular afterload. Sarcomeric mutations represent the most common genetic cause in children and adults with a detection rate of about 60% in childhood HCM diagnosed beyond the first year of life, similar to that of adult HCM patients . By compHCM forms the second commonest group of childhood cardiomyopathies, comprising 25–42% of all cases, respectively. The overall annual incidence is 0.24–0.47 per 100,000 children see  7, 17, , 17, 18.The clinical status at presentation ranges from asymptomatic to symptoms of exercise intolerance, chest pain, palpitations, syncope, or cardiac arrest . CongestThe natural history and outcome of childhood HCM largely depend on the age at presentation and the underlying aetiology. The highest risk of mortality is seen in those diagnosed during the first year of life .Overall survival free from death or transplantation was found to be about 90% at 5 years and 78% at 20 years from presentation see  6, 8, 2. The risThe worst outcomes are in infants with heart failure at the time of diagnosis and in older children with marked restrictive pathophysiology. Other risk factors include concentric left ventricular hypertrophy at diagnosis, Noonan syndrome, and increasing LV ventricular free wall thickness and worsening LV systolic function during follow-up . In the While congestive heart failure accounts for the majority of early deaths in childhood HCM, the most common mode of death overall is SCD , 8. ArrhRestrictive cardiomyopathy (RCM) is a rare form of heart muscle disease defined by “normal or decreased volume of both ventricles associated with biatrial enlargement, normal left ventricular wall thickness and atrioventricular valves, impaired ventricular filling with restrictive physiology, and normal  systolic function” . Nearly RCM is the rarest form of paediatric cardiomyopathy with an incidence of 0.03–0.04 per 100,000 children in Australia and the United States see  7, 17)., 17.7, 1Early symptoms of RCM may be non-specific, including general fatigue and exercise intolerance. Clinical findings secondary to elevated systemic and pulmonary venous pressures include peripheral oedema, hepatomegaly, pulmonary oedema, and pulmonary hypertension . In the Whilst RCM has the worst outcomes of any childhood cardiomyopathy, the natural history has largely been obscured by early referral for transplantation. Long-term transplant-free survival data is therefore sparse. Because of its relentless and progressive nature, patients are at risk of sudden death, congestive heart failure, atrial and ventricular arrhythmias, conduction disorders and thromboembolism , 52. Traz-score at diagnosis were identified as independent risk factors for decreased transplant-free survival  is a heterogenous form of cardiomyopathy characterised by excessive trabeculation of the left or both ventricles with deep intertrabecular recesses, most frequently affecting the left ventricular apex. LVNC was classified as a separate cardiomyopathy by the American Heart Association in 2006  however The rates of diagnosis of LVNC in children have increased during the last decades, which is thought to reflect increased awareness and improved imaging techniques rather than a rise in incidence . Data frPatients with LVNC may be found on routine screening but may also present with thromboembolic events, arrhythmias, or congestive heart failure . The varThe outcome of paediatric LVNC is highly variable and depends on the underlying pathophysiology . BresciaOver the last 2 decades, registries and national studies have provided important data on epidemiology and outcomes of childhood cardiomyopathies. The reported overall annual incidence was between 0.65 and 1.24 per 100,000 children , 17, 18.LVNC cardiomyopathy has increasingly gained attention over the last two decades and there is ongoing discussion with regards to its diagnostic criteria , 26. IncWhile there has been a dramatic improvement in survival of congenital heart disease over the last decades, the overall outcomes for childhood cardiomyopathies remain unfavourable , 59. RecPaediatric cardiomyopathies, although rare, carry a substantial burden of disease due to the risk of morbidity and mortality and a lack of curative therapy. Established registries have provided valuable insights into the natural history and risk factors, assisting in decision-making on sudden cardiac death prevention and cardiac transplantation.AR drafted the manuscript and designed figures and tables. RW supervised the project and contributed substantially to the final version of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dysfunction of the left ventricle (LV) with impaired contractility following chronic ischemia or acute myocardial infarction (AMI) is the main cause of ischemic mitral regurgitation (IMR), leading to moderate and moderate-to-severe mitral regurgitation (MR). The site of AMI exerts a specific influence determining different patterns of adverse LV remodeling. In general, inferior-posterior AMI is more frequently associated with regional structural changes than the anterolateral one, which is associated with global adverse LV remodeling, ultimately leading to different phenotypes of IMR. In this narrative review, starting from the aforementioned categorization, we proceed to describe current knowledge regarding surgical approaches in the management of IMR. The right coaptation of mitral valve (MV) leaflets is achieved thanks to the balance between closing forces generated by contraction of the left ventricle (LV) and tethering forces of the subvalvular apparatus preventing leaflet prolapse into the atrium .Secondary mitral regurgitation (SMR) is a consequence of geometrical modification of the mitral valve (MV) apparatus without leaflet abnormalities.Dilated cardiomyopathy (DCM), regardless of its etiology, often leads to SMR, due to the changes in LV shape . AccordiImpaired LV contractility due to chronic ischemia or acute myocardial infarction (AMI), often in the context of heart failure with reduced ejection fraction (HFrEF), leads to moderate and moderate-to-severe mitral regurgitation (MR) in 50% and 10% of patients, respectively ,4,5.IMR is mainly caused by: 1) the reduction of systolic closing forces because of the impaired LV function, (2) the displacement of papillary muscles (PM) caused by LV dilation, which increases MV leaflet tethering forces, widely recognized as the predominant causative mechanism [ the reduThe site of AMI exerts a specific influence determining different patterns of adverse LV remodeling. In general, inferior-posterior AMI is more frequently associated with regional structural changes than the anterolateral one, which is associated with global adverse LV remodeling ,6,7.As proposed by Packer et al. , global Therefore, the natural history of this phenotype of IMR shares a strong association with LV dysfunction and hemodynamic factors, being a predictor of adverse outcomes.Vice versa, a disproportionate degree of MR, compared to LV dysfunction, characterizes IMR when PMs undergo asymmetrical impairment. In general, asymmetric leaflet tethering is determined by the functional involvement of the posteromedial PM as in regional LV remodeling occurring after inferior-posterior AMI. Although the chordae from the posteromedial PM are anchored to both leaflets, tethering of the posterior leaflet results in a worse distortion of mitral valve geometry.Alternatively, in a globally dilated LV, delayed activation of anterolateral PM  as occurs in the left bundle branch block (LBBB) may represent the leading cause of asymmetric tethering ,9.This classification may have a crucial role in the correct management of IMR and we have graphically simplified it in the Therefore, a detailed diagnostic assessment is of paramount importance. Imaging characteristics of IMR phenotypes may be a useful guide to take into account, to systematically consider the different management options.Echocardiography is the most widely used investigation to diagnose MR, allowing the description of the etiologic and functional mechanism and the assessment of the severity of valvular regurgitation.2 and RVol of >30 mL are enough to define severe MR. US guidelines consider higher values of both EROA and RVol for MR severity [According to the recent European guidelines, established criteria to diagnose severe SMR are based on the echocardiographic measures of Effective Regurgitant Orifice Area (EROA) and regurgitant volume (RVol), but with lower cut-off values if compared with those for primary or organic MR; in particular EROA of >20 mmseverity ,11,12.The integration of multiple techniques and parameters, including three-dimensional (3D) echocardiography assessment, is necessary to perform a comprehensive analysis .MR deriving from asymmetric tethering of mitral leaflets is characterized by an eccentric and posteriorly directed jet of regurgitation; a peculiar feature of “hockey stick”, obtained by the apical and posterior movement of the tip of the posterior mitral leaflet. The “pseudo-prolapse” of the body of the anterior one is emblematic too.On the contrary, the involvement of PMs by global dilatation of LV in the absence of mechanical dyssynchrony leads to their equal displacement and to symmetric tethering of both mitral leaflets. Qualitatively, the coaptation line is displaced apically and the resultant regurgitant jet is central ,15,16,17Besides phenotypical categorization and magnitude of LV impairment, tethering of MV leaflets is the invariable factor characterizing IMR, making it crucial for the quantitative assessment of displacement measures to predict the severity of MR, as illustrated in This narrative review was designed with the aim of comprehensively categorizing the invasive methods in the management of IMR. In particular, tailored surgical techniques addressing the aforementioned tethering phenotypes are described in the following paragraphs. PMs dysfunction leading to MR was first described by Philips et al. , providiA growing pathophysiologic complexity followed the categorization proposed by Miller et al. , who demIMR reflects different grades of LV dilatation associated with distortion of MV geometrical configuration, which potentially involves the whole apparatus.The best surgical approach, finalized to restore MV geometry, still remains under debate.The classification proposed by Carpentier  has provRestriction of MV leaflet mobility during systole and mitral annulus dilatation, without detectable primary lesion to the integrity of MV leaflets and subvalvular apparatus, are the functional alterations found in IMR, therefore categorized as type IIIb and type I.Consequently, for many years, mitral valve annuloplasty (MVA) has been the cornerstone of MVRepair, although in absence of a complete understanding of the pathophysiology of IMR and well-established surgical principles.The goal of this section is to offer a systematic understanding of the most widely used MVRepair techniques in the treatment of IMR, focusing on recent evidence. Excluded from the discussion are surgical techniques at the ventricular level, external ventricular re-shapers and others, that even if they have achieved good results, are limited by a lack of experience. In particular, two different extracardiac devices were initially introduced achieving satisfactory outcomes. The CorCap  cardiac support device, which has demonstrated in the Acorn trial to potentially restore LV shape when associated to restrictive mitral valve annuloplasty (rMVA) with sustained effects after 3-year and 5-year follow-ups ,24,25.The Coapsys , an extracardiac device with the aim to reduce the septolateral mitral dimension and reshaping LV, has demonstrated to be effective, although in a small sample size, to improve EF and reduce MR grade .Different types of MVA techniques and annuloplasty rings were initially used in order to restore the morphology of native mitral annulus (MA) and to prevent further annular dilatation, similarly to primary MR.The major findings of studies evaluating the effectiveness of MVA are reported in In patients with IMR who underwent coronary artery bypass graft (CABG), the effectiveness of adjuvant MVA to reduce the grade of regurgitation was reported, although showing an absolute unsatisfactory postoperative survival with early mortality and 5-year survival on average of 13% and 50%, respectively ,38,39,40Bolling et al.  first inPostoperative survival was surprisingly higher than former reports which adopted non-downsized MVA, with early mortality and 2-year survival being 2.1% and 72%, respectively.The concept of rMVA was later largely adopted by other surgeons, showing good results in terms of early mortality and 5-year survival, reaching values of approximately 5% and 70%, respectively ,43,44. RAlthough rMVA -downsizing the mitral annulus by two sizes than the one indicated by the inter-trigonal distance- has been successfully introduced among the tailored surgical strategies for treatment of IMR, discordant results concerning postoperative survival made a correct stratification of eligible patients necessary ,45.Interestingly, Braun et al. , albeit Di Gianmarco et al.  found thThe authors further reported results of etiological subgroups analysis of patients with secondary MR, confirming worse long-term outcomes in the group with IMR compared to those with FMR due to idiopathic DCM.Lacking strict selection criteria, persistence or recurrence of MR after rMVA have been reported with high frequency, representing a consistent limitation, leading to poor survival, even though the repair technique is highly reproducible and relatively easy ,47.The progressive and irreversible dilatation characterizing the advanced stage of DCM was recognized as the leading mechanism underlying technical failure. Nevertheless, the worse outcomes associated with the management of ischemic DCM reflected the need to carefully analyze leaflet configurations after surgical annuloplasty.Zhu et al.  concludeDistortion of mitral valve geometry gained a leading role when Magne et al.  demonstrPatients with PL angle ≥45 degrees, a common echocardiographic finding in the asymmetric tethering of leaflets, showed poor 3-year event-free survival and increased risk of an adverse cardiac event. Instead, in absence of residual MR soon after surgery, more accentuated tethering of AML was identified as the independent predictor of MR recurrence at follow-up. Gelsomino et al.  demonstrThese observations pointed out the paradoxical increase in MV geometry distortion due to asymmetric subvalvular apparatus tethering and the decisive role of meticulous echocardiographic assessment.2 and tenting height (TH) ≥ 1.1 cm have been reported as valid predictive variables of technical failure [Additionally, when global LV dilatation is observed, a pathophysiological substrate underlying symmetric tethering, in addition to PL angle, tenting area (TA) ≥2.5 mm failure ,43.In these patients, rMVA and the underlying surgical principle of overreduction, moving the posterior leaflet anteriorly with implantation of a symmetric and flat annuloplasty ring, was not sufficient to ensure proper coaptation of the leaflets during systole ,30,48.A new remodeling annuloplasty ring was designed with the purpose to act directly on the asymmetric deformation of the MV apparatus that often characterizes type IIIb ischemic MR . It was The introduction of an etiology-specific annuloplasty ring was a big step forward in the standardization of rMVA as a tailored surgical technique for IMR, which until that point was performed without an appropriate indication on the type of ring to be used.Targeting the aforementioned asymmetric restriction of mitral leaflets, CMA IMR ETIlogix differs from the classical Physio-Ring prosthesis  which is flat and symmetrical, in the reduction of the posteromedial axis and configuration with smaller and depressed P2-P3 scallops .The new annuloplasty ring showed excellent results significantly reducing mitral annulus diameters (MAD), TA and TH, proving to be effective in annular remodeling, in reducing leaflet tenting and in restoring leaflets coaptation.The modifications produced on mitral valve geometry demonstrated a paramount impact in reducing early postoperative persistence and recurrence at follow-up of MR in patients with IIIb ischemic MR who underwent MV repair with the implantation of CMA IMR ETIlogix ,32,34,36In addition to this remodeling annuloplasty prosthesis, the GeoForm ring  has been specifically designed for the surgical treatment of secondary MR; in particular, targeting the phenotype with symmetrical restriction of both mitral leaflets, caused by ischemic or idiopathic DCM.The three-dimensional configuration of the GeoForm ring is characterized by notably reduced septo-lateral diameter, which does not make it suitable for prevalent tethering of PML, and by a posterior indentation designed to enhance leaflet coaptation and counteract subvalvular remodeling.Votta et al. , by usinIndeed, in comparison, the Physio ring showed to require consistent undersizing to induce coaptation, causing distortion of the inter-trigonal tract, potentially altering the aortic valve mechanism and being less effective to reduce leaflet stress, mostly in severe MR.Satisfactory results were later shown by De Bonis et al. , who repThough at 3.5 years, overall freedom from MR ≥ 2+ was 75.1 ± 8.6%, excellent outcomes were achieved considering MR with symmetric pattern of tethering, unlike predominant restriction of PML, showing a rate of persistent/recurrent MR ≥ 2+ of 9% rather than 33%, respectively.In addition, the implantation of GeoForm® ring  was not associated with clinically relevant mitral stenosis, in spite of a remarkable reduction of the septo-lateral diameter .Instead, after surgical annuloplasty performed with the Physio ring , it was common to detect mitral stenosis (MS), labeled as “functional” for the absence of structural abnormalities of mitral leaflets, generally attributed to excessive reduction of annular size. Interestingly, the degree of functional MS was significantly related to -besides NYHA functional class- recurrent MR, emphasizing the role of postoperative subvalvular tethering in globally influencing the functionality of mitral leaflets .The encouraging outcomes reported were later confirmed by Timek et al. , who pubAlthough the heterogeneity of patient population with almost 30% of MR grade 2+ and the great percentage of missing echocardiographic follow-up data has to be taken into account, freedom from MR ≥ 2+ at 5 years was 86%; further showing a significant impact on LV reverse remodeling with a significant increase in ejection fraction (EF) and decrease in LVEDD and LVESD, respectively.In a recent meta-analysis, Micali et al.  have invAlthough the study failed to identify a significant difference between ring type, rigidity/flexibility and symmetry, the best performance has been achieved by implantation of IMR-ETIlogix  which showed the lowest rate of recurrent MR (6%), followed by GeoForm® ring  (12%), after a mean follow-up period of 3.3 years.The superiority of these etiology-specific annuloplasty rings may be ascribed to the ring design, which targets the different pattern of valve leaflet tethering, allowing inducing tailored changes in the geometry of MA effective to restore proper leaflet coaptation.However, the meta-analysis, considering LVEDD at follow-up as an index for ventricular remodeling due to widely missing data about LV volumes, showed no significant LVRR after rMVA, confirming the ineffectiveness in countering LV remodeling reported by other authors ,53,54.Over the years, alongside annuloplasty, different techniques for the surgical correction of IMR to restore mitral valve continence have been proposed.In particular, papillary muscle intervention (PMI), which has been met with greater consensus, and chordal cutting (CC) have been introduced with the purpose of counteracting the excessive tension on chordae produced by displacement of PMs .In achieving this, Kron et al.  first deThe concept of reducing the excessive tethering on mitral leaflets was differently approached by Hvass et al. , who proInitially, sharing the same surgical principle and ensuring good results when performed in addition to rMVA, surgeon preference and experience were the major determinants of choice between the two aforementioned techniques .Equivalence in terms of outcomes was subsequently reported by Furukawa et al. , showingThe impact of PMIs in IMR was investigated in a recent meta-analysis published by Micali et al. , compariThe combined surgical approach showed a significant lower incidence of MR recurrence, highlighting the importance of correcting the primary pathophysiologic mechanism underlying MR.In particular, PMs repositioning technique has been demonstrated to be more efficient than PMA to counteract subvalvular apparatus distortion and to allow more normal leaflet valve mobility ,65.These findings may be in contrast with the report published by Furukawa et al. , as explIMR is more frequently associated with asymmetric distortion of subvalvular apparatus, thus using the PMA technique, having as purpose the realignment of PMs symmetrically toward LV mid-portion, is often not appropriate to counteract the direction of tethering forces. Therefore, the use of the PMA technique should only be adopted after an accurate echocardiographic assessment of the pathophysiologic mechanism underlying FMR, identifying correctly the geometry of both the valve apparatus and LV .Conversely, the meta-analysis failed to show a significant impact on LV geometry, with a reduction of LVEDD at follow-up, though slightly higher in the PMI + MVA group, still below the cut-off considered for LVRR.Therefore, what emerged is the superiority of a surgical approach at the subvalvular level, which further allows decreasing leaflet stress distribution avoiding the use of an excessive downsized annuloplasty ring.2 and Rvol ≥ 30 mL.Fattouch et al.  showed eUnlike the growing evidence supporting PMI as the adjunctive technique for the management of IMR, the benefit carried by chordal cutting (CC) is yet questionable, requiring an expansion of the limited current knowledge.The surgical principle underlying second-order CC is to increase leaflets valve mobility eliminating excessive forces of tethering.Although clinical reports, showing good results in terms of MR recurrence and LV function, have drawn a positive consensus, controversies are mainly related to the key role played by second-order chords in connecting and ensuring stability to the main components of the MV apparatus ,69,70.Interestingly, Calafiore et al.  demonstrAs hypothesized by the same authors, it seems that second-order chords have a different role from that observed in a normal setting, leading to excessive tethering and increased leaflet peak stress, paradoxically worsening LV function.In conclusion, surgery at the subvalvular level may confer long-term durability to MVRepair, potentially reversing LV adverse remodeling. The strength of this surgical approach may be identified in the possibility of treating every single IMR phenotype in a tailored manner; the weakness lies instead in the difficulty to make the techniques easily reproducible.The major findings of afore-described studies are reported in While emphasizing the efficacy of the surgical approach that combines MVA and surgery at the subvalvular level, intervention based on the concept of “mitral plasticity” should be briefly described.This latter has been recently introduced with the purpose to describe the mechanisms adopted by the MV apparatus to compensate mechanical tethering caused by chronic ischemic LV remodeling.Indeed, displacement of PMs triggers a series of molecular and structural changes in the MV, leading to increased length of valve leaflets, mainly the AML, and chordae tendineae, in order to allow proper coaptation. Interestingly, this adaptive process has manifested to have a variable expression with subjective clinical characteristics, showing significant IMR when it fails to provide valve competence ,73,74.Surgical mitral plasticity consists in the approach that plans to complete these modifications when not adequate to balance LV remodeling, including rMVA, CC and AML augmentation, has been proposed by Calafiore et al. .Although surgical techniques based on leaflet augmentation, using the pericardial patch, had already been used in the past, mid-term outcomes obtained were unsatisfactory ,77,78. IA significant benefit to valve leaflet mobility through the addition of second-order CC able to restore normal leaflet curvature, besides improvement of the LV function, has been demonstrated by post-operative echocardiographic findings .Although these results bode well, studies with a larger sample and longer follow-up are needed in order to introduce surgery at the valvular level in the tailored management of IMR.The impact of correction at subannular level on LV function and MR recurrence, as recently evidenced, and its reduced use may help to better understand the discordant results in the study of MVRepair when compared with mitral valve replacement (MVR).p = 0.01) [Cardiothoracic Surgical Trials Network (CTSN) randomized studies, designed to evaluate LVRR as the primary endpoint, compared rMVA versus MVR with preservation of the subvalvular apparatus at 2-year follow-up. They fail to observe differences in terms of LVRR and survival rate between these two surgical strategies, showing an increased number of cardiovascular readmissions in the MVRepair group ( = 0.01) ,80.However, an unequal distribution of concomitant CABG procedures among subgroups object of analysis (rMVA vs. MVR) has been reported as potential bias in the correct interpretation of data .Until then, although a series of unpowered studies were reported in the initial experience, there was a consensus towards MVRepair and particularly in performing the high-reproducible technique of rMVA ,81,82.In contrast, a higher rate of MR recurrence, reflecting the absence of tailored techniques on valvular anatomy, as discussed in the previous section, worsened outcomes in terms of LV function and long-term survival.Magne et al.  reportedDifferent types of annuloplasty rings were implanted in the Italian Study on the Treatment of Ischemic Mitral Regurgitation (ISTMIR), including ETIlogix and GeoForm® ring , specifically projected for SMR. No differences between MVRepair and MVR were found in early and late survival at 8-year follow-up and potential effects on LV performance .Despite surgical principles and technical aspects, stratification of eligible patients was not-well established leading to inhomogeneous distribution among groups.In this context, Chan et al. , studiedTherefore, methodological studies, enlarging the analysis to include current surgical strategies in MVRepair and through detailed characterization of MV apparatus geometry among others, are necessary to improve our knowledge concerning the surgical approach of IMR.Nevertheless, the choice of MVR rather than MVRepair, which more often allows a tailored restoration of MV function, specifically counteracting changes in geometry, is still an open question.Extreme tethering of PML angle (>45°);Complex multiple regurgitant jets;2, CD >18 mm);Excessive bileaflet tethering  may be a viable option. Indeed, it leads to a notable reduction of low-cardiac output syndrome (LCO) incidence due to the maintenance of valvular-ventricular apparatus which modulates distension and wall tension of LV during the cardiac cycle .Findings from major studies reported are summarized in The multifaceted complexity of IMR not only requires an appropriate choice between treatment options but also correct management timing.As exposed in the introduction, moderate IMR complicated up to 50% of cases of patients affected by myocardial infarction (MI), definitely leading to the adverse outcomes and poor prognosis ,10.In HF patients with reduced ejection fraction (HfrEF), an increase in the severity of SMR was reported as predictive factor leading progressively to adverse events .2; Rvol = 30 mL according to US guidelines), whose etiology mostly varies from ischemic injury to HF, exacerbates primary conditions, over the years, evidence failed to show any advantages in its adjunctive surgical management concomitant to CABG , in order to improve MV competence, consists of tissue approximation leading to the increased surface of coaptation, recognizing its forerunner in the surgical suture-based approach .This latter has been introduced by Alfieri in 1991 and labeled as edge-to-edge surgical technique, initially targeting cases of severe MR in which, due to peculiarity of the lesion, the traditional techniques of reconstruction were challenging .MitraClip is based on a transcatheter approach, including a clip system delivered into the left atrium through a transeptal puncture performed in the fossa ovalis.Three-dimensional trans-esophageal echocardiogram (TEE) represents the essential tool both to guide towards a detailed assessment of MV anatomy and to target the lesion .Reduction of MR may be achieved by correct positioning of the clips between free edges of leaflets and the subsequent release.The feasibility of the procedure with a percutaneous approach and the reversibility of implantable clips, with the intraoperative possibility of repositioning them until obtaining the satisfactory results, have favored the large diffusion of MitraClip .The EVEREST II trial  was desiIn contrast, percutaneous repair has been demonstrated to be superior in safety at 30 days, with the rate of major adverse events 3-fold higher in the surgery arm and to achieve similar clinical outcome improvements . NeverthThough controversies have accompanied EVEREST II trial findings, important considerations have been drawn from subgroups analysis, based on the pathophysiology of MR, which have sharply marked the MitraClip future application.Indeed, in the small subgroup of patients with secondary MR, both percutaneous and surgical MV repair were associated with similar outcomes.Therefore, the need for an accurate stratification of eligible patients began to be clear.Baldus et al.  reportedPatients were selected by the Heart Team mainly for the prohibitive risk for the surgical approach, showing low in-hospital mortality (2.5%) but considerable post-discharge mortality (12.5%) with a median follow-up of 3 months, reflecting the advanced stage of the disease.Similarly, Maisano et al.  enrolledTechnical feasibility, procedural safety and clinical efficacy by using MitraClip have been the benefit reported more recently by Geis et al. , who demResults from two randomized trials MITRA-FR  and COAPT  have been published ,112.The trials have been designed to compare MitraClip in addition to optimal medical therapy (OMT) (intervention group) and OMT alone (control group) in the management of patients with systolic HF and secondary MR.Although COAPT trial showed the effectiveness and safety analysis better in the intervention group, MITRA-FR fails to demonstrate any improvements in the prognosis of patients treated with percutaneous MV repair in comparison with the control group ,112.Several commentaries tried to explain the discordant results obtained by these two trials, apparently designed with an equal setting, sharing the same basic ideas.Indeed, patient selection, percutaneous procedures and medical treatment process are recognized as the main criticisms ,114,115.2 vs. 0.31 cm2), characterizing treated cases for a disproportionate grade of MR when correlated to LV adverse remodeling, as postulated by Grayburn et al. [In comparison to MITRA-FR, LV size in COAPT was smaller whereas FMR was more severe  in the setting of significant LV dysfunction are yet available.Cardioband system  is a transcatheter-based approach mimicking the traditional annuloplasty, in which the device is directly delivered into the left atrium through the femoral vein and a transseptal puncture .In contrast, the Carillon™ Mitral Contour System™  encircles MA indirectly being delivered in the coronary sinus (CS) through access performed in the external jugular vein .Similarly to MitraClip, the target population is represented by surgical high-risk profile patients with symptomatic FMR despite OMT.Experience with these devices is still limited, although results are encouraging.Cardioband system  showed better clinical outcomes at 12 months follow-up when compared with the MitraClip device ,121.In a randomized trial, the Carillon device has demonstrated its safety and efficacy to significantly reduce MR and LV volumes in symptomatic FMR patients when added to OMT .Differently from transcatheter aortic valve implantation (TAVI), MV replacement with trans-catheter therapy has not achieved clinical consensus due to the complexity of MV anatomy and disease pathophysiology.Mainly for this reason, although several devices have been described in the literature, the use of TMVI is still limited to compassionate use or very high-risk patients .The rationale at the basis of the use of cardiac resynchronization therapy (CRT) in the management of IMR, consists in counteracting restriction of MVL, increasing closure forces .Indeed, Kanzaki et al.  recognizIn confirming the acute effects of CRT to target PMs dyssynchrony, changes in echocardiographic parameters of IMR severity have been reported, reduction of ERO among others, reflecting the improved clinical status of patients ,128,129.In addition, the restoration of physiological electrical sequence has demonstrated a long-term effect, after 3–6 months of CRT, on LV dimensions and shape, leading to LVRR and increasing global contractility, further improving MV competence .The direct correlation at long-term between LV remodeling and FMR improvements has been confirmed by Verhaert et al. , who furSimilarly, Van Bommel et al.  reportedIn contrast, predictors of technical failure are still poorly understood due to the complexity of the condition, not allowing definitively the standardization of this technique in the tailored management of IMR in HF patients with LBBB.Dibiase et al.  showed t2 the strongest predictor of MR persistence, expression of high grade IMR. Excessive dilatation of LV was identified by Ohnishi et al. [Sitges et al.  found ini et al.  togetherInterestingly, Gavazzoni et al. , with thIMR, regardless of its severity, represents an independent predictor of poor outcome.MVA has been the first widely used MVRepair technique in the surgical approach of severe IMR. Criticisms associated with technical failure and the long-term durability of this approach associated with the growing pathophysiologic knowledge, mainly related to echocardiographic developments, have been the catalytic factors that moved towards a targeted surgical approach.Gradually, the flat and symmetrical annuloplasty ring was replaced by prosthesis which reflected the MV geometrical changes, as seen with CMA IMR ETIlogix and GeoForm annuloplasty rings, achieving better results in terms of MR recurrence at early and late follow-up after surgery.In contrast, concomitant MVA and sub-valvular surgical correction, including the afore reported techniques in targeting MV apparatus abnormalities, may restore a more physiologic configuration.The surgical approaches addressing PMs, although limited by still low sample size, have demonstrated superior outcomes in reducing the restriction of mitral leaflets, increasing MV competence and mainly in having an impact on LV volumes and contractility.Therefore, a comprehensive approach to severe IMR should be addressed first to properly categorize MV structural changes, allowing to quantify geometrical distortion of valve apparatus, further evaluating echocardiographic parameters potentially predictive of technical failure. Quantitative echocardiographic measurements such as CD, MVTa, TnV, interpapillary distance among others, should be followed by an accurate assessment of tethering angles and degree of leaflets restriction.Echocardiography should offer itself as a direct line toward the possibility of a combined surgical approach, including MVA and subvalvular surgery when feasible, as the preferred choice of management ,141,142.On the other hand, the excessive geometrical distortion of MV, in particular affecting the length and mobility of valve leaflets, or a significantly dilated LV, which increase the risk of technical failure, may be the indication to choose MVR. In patients requiring surgical revascularization, with moderate IMR, due to the long-term poor prognosis and the demonstrated ineffectiveness achieved by MVA alone, surgical approach to MV could be avoided.In the modern era of the percutaneous approach, minimally invasive techniques such as MitraClip have been largely used, even though the poor understanding of the complexity of IMR.The consistent experience achieved in performing MVA has demonstrated that surgical correction performed at the annular level is not enough to provide long-term durability of the repair.In contrast, CRT offers a different point of view in the management of IMR, even though requiring a proper categorization of eligible patients, it needs to be encouraged in the context of a combined surgical approach.


Background: There have been no systemic studies about right heart filling pressure and right ventricular (RV) distensibility in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Therefore, we aimed to explore combinations of echocardiographic indices to assess the stages of RV diastolic dysfunction.Methods and Results: We recruited 32 healthy volunteers and 71 patients with CTEPH. All participants underwent echocardiography, cardiac catheterization (in patients with CTEPH), and a 6-min walk test (6MWT). The right atrial (RA) end-systolic area was adjusted for body surface area (BSA) (indexed RA area). RV global longitudinal diastolic strain rates (SRs) and RV ejection fraction (EF) were measured by speckle tracking and three-dimensional echocardiography (3D echo), respectively. All 71 patients with CTEPH underwent pulmonary endarterectomy. Of the 71 patients, 52 (73%) had decreased RV systolic function; 12 (16.9%), 26 (36.6%), and 33 (46.5%) patients had normal RV diastolic pattern, abnormal relaxation (stage 1), and pseudo-normal patterns (stage 2), respectively. The receiver operating characteristic curve analysis showed that the optimal cut-off values of early diastolic SR <0.8 s−1 and indexed RA area > 8.8 cm2/BSA had the best accuracy in identifying patients with RV diastolic dysfunction, with 87% sensitivity and 82% specificity. During a mean follow-up of 25.2 months after pulmonary endarterectomy, the preoperative indexed RA area was shown as an independent risk factor of the decreased 6MWT distance.Conclusions: Measuring early diastolic SR and indexed RA area would be useful in stratifying RV diastolic function. Pulmonary arterial hypertension (PAH), left heart failure (HF), mechanical ventilation, and left ventricular assist device implantation are associated with right HF –3. EarlyRecently, Mele et al.  reportedOur study aimed to explore echocardiographic parameters in assessing RV diastolic function, to prove the correlations between the right heart filling pressure and stages of RV diastolic function, and to observe the outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy.The Institutional Review Board of Fuwai Hospital approved the study protocol , which was in accordance with the “Declaration of Helsinki.”In total, 71 patients  who were diagnosed with CTEPH at Fuwai Hospital between January 2018 and June 2020 were included. Their diagnosis was based on echocardiography, CT, and cardiac catheterization. None had a history of cancer. All these patients underwent pulmonary endarterectomy. Pre- and post-operative medical records of patients with CTEPH were collected.Thirty-two healthy volunteers  with no history of heart or lung diseases or symptoms and with normal physical examination findings were selected as control participants. Written informed consent was obtained from all participants.Transthoracic echocardiography was performed using a 3–4.5-MHz transducer . Measurements were performed according to the American Society of Echocardiography guidelines for the assessment of heart chambers . The rigMitral and tricuspid inflow velocities were recorded. These parameters included early filling velocity (E), atrial filling velocity (A), E/A ratio, and deceleration time (DT). Mitral and tricuspid annular systolic velocity (s'), early-diastolic velocity (e'), and late-diastolic velocity (a') were assessed in the apical four-chamber view. The RV index of myocardial performance (RIMP) was defined as the ratio of the sum of the isovolumic contraction time and the isovolumic relaxation time (IVRT) divided by the ejection time.Images were further analyzed using two-dimensional speckle echo software  with a calculation of RV global longitudinal strain (GLS), and early and late diastolic strain rates (SRs) for the entire traced contour of the right ventricle . MeasureThree-dimensional echocardiography (3D echo) was performed at the cardiac apex using a matrix-array transducer (4VC). All images were analyzed by four-dimensional RV analysis software . RV end-diastolic volume (EDV) and RV end-systolic volume (ESV) were obtained. RV ejection fraction (EF) was then measured as the percentage change of the volumes.Right ventricular systolic dysfunction was defined when at least two parameters were below the lower recommended limit of normal   curve analysis. The chi-square test was used to compare proportions. Differences were considered significant if the p < 0.05.SPSS 24.0 was used for statistical analysis. Results were expressed as mean (±standSD) unless stated otherwise. When comparison among three groups was needed, a one-way ANOVA was carried out. The independent samples The baseline characteristics of all control participants and medical records of patients with CTEPH are shown in R = 0.67 and 0.68, both p = 0.0001), IVRT , TV annular e' , early diastolic SR , and indexed RA area . The linear regression model showed that the indexed RA area was mostly impacted by increased PASP  and mean PAP , including RIMP, IVRT, TV e', early diastolic SR, indexed RA area, TV E/A ratio, TV E/e' ratio, and TV DT . Furthermore, early diastolic SR <0.31 s−1 and indexed RA area >10 cm2/m2 could further separate stage 2 RV diastolic dysfunction from stage 1, with sensitivities of 74% and 74%, and specificities of 27 and 53%, respectively.Receiver operating characteristic curve analysis showed that the optimal cut-off values of early diastolic SR <0.8 sectively . RV diasp = 0.08) and 11.86 (p = 0.003). When early diastolic SR, indexed RA area, RIMP, and IVRT were added, the detection rate of RV diastolic dysfunction was increased, with chi-square values of 6.71 (p = 0.03) and 5.36 (p = 0.04).p = 0.002). Univariate logistic regression analysis showed that only preoperative indexed RA area was significantly associated with the decreased 6MWT distance during follow-up among all related factors, including preoperative mean PAP, PASP, TR degree, early diastolic SR, RIMP, IVRT, the follow-up PASP, and TR degree (p = 0.023). Furthermore, the multivariate logistic regression model found that the preoperative indexed RA area was an independent risk factor of the decreased 6MWT distance during follow-up (We followed 68 patients with CTEPH from 1 to 45 (25.2 ± 9.3) months after pulmonary endarterectomy. Three patients were lost for follow-up after discharge. During the follow-up period, three late deaths occurred (4.4%). One patient died from advanced gastric cancer with gastrointestinal hemorrhage, and two patients died from a lung infection, probably related to residual pulmonary hypertension. Furthermore, 61 of 65 patients (93.8%) were in NYHA I or II. Among the 65 patients, 57 (87.7%) patients had mild or trace TR, five (7.7%) patients had mild-to-moderate TR, and the remaining three (4.6%) patients had moderate TR. Finally, 34 of 63 (54%) patients completed the 6MWT during follow-up. Compared with the 25 patients with a 6MWT distance ≥450 m, the nine patients whose 6MWT distance ranged from 375 to 499.9 m had a larger preoperative indexed RA area  early diastolic SR and indexed RA area were useful in stratifying RV diastolic dysfunction; (2) stages of RV diastolic dysfunction were related to the degree of the increased right heart filling pressure, and (3) preoperative indexed RA area could predict postoperative 6MWT distance.The criteria recommended by the American Society of Echocardiography for RV diastolic function evaluation have been described, with differences in the E/A ratio, E/e' ratio, and DT. However, some patients had overlapping E- and A-waves and were markedly influenced by the respiratory cycle, especially the patients with PAH or CTEPH. Consequently, this would hamper the assessment of the appropriate and reproducible RV diastolic function.In an earlier report from our laboratory, we found good correlations between PASP and echocardiographic parameters assessing RV diastolic function . Our evaOur study found that RV-impaired relaxation pattern (stage 1) mostly occurred in patients with CTEPH with normal right heart filling pressure. The proportion of patients with stage 2 RV diastolic dysfunction was higher among those with the increased right heart filling pressure. RV diastolic dysfunction was an early sign of myocardial remodeling in CTEPH, and it presented earlier than the actual increase in RA or ventricular filling pressure .3) for separating normal from elevated mean RAP (>8 mmHg) was approximately 90%. A Canadian study (2) and RA area (>20 cm2) could detect elevated RV end-diastolic pressure with a sensitivity of 90% and a specificity of 80%. Our study confirmed that indexed RA area >8.8 and >10 cm2/m2 were helpful to identify stage 1 and stage 2 RV diastolic dysfunction. Unlike the findings of previous studies, we measured the indexed RA area, instead of the indexed RA volume, since the accuracy of RA volume was limited. Until now, the three-dimensional echo software, which is used to measure RA volume, is developed for LV analysis.In the chronic setting, as the ventricle thickens, RV filling becomes more dependent on RA performance driven by progressive perturbation of the normal Frank-Starling mechanism to preserve cardiac output. With RV deteriorating diastolic function, increased RA contractility and right heart filling pressure caused the RA chamber to distend. Maniar et al.  reportedan study  showed tThe early rapid and active filling depends more on the ventricular myocardial relaxation which could be assessed by SR accurately –17. OkumThus, the indexed RA area and early diastolic SR could be used to evaluate the stages of RV diastolic function, especially when the E/A and E/e' ratios could not be accurately obtained. To enhance the accuracy and reliability of RV diastolic dysfunction assessments, the new diagnostic model was tested based on at least two abnormal results of the four novel parameters in this study, including indexed RA area, early diastolic SR, RIMP, and IVRT.Recent data suggested that decreased 6MWT was associated with lower LV EF, LV diastolic dysfunction, and increased left atrial dimensions , 20. SomThis is a single-center study, albeit prospective, with some limitations. RV diastolic function is determined by multiple factors at the cellular, myocardial, and heart chamber size levels. Right heart filling pattern and filling pressures reflect the net balance of many variables. It is difficult to capture all these variables by either invasive or non-invasive techniques. We feel that RV diastolic dysfunction could not be adequately assessed by a single parameter. Some investigators suggested that a diastolic RV pressure increase by >4 mmHg or end-diastolic pressure >10 mmHg could define RV diastolic dysfunction, but we did not measure pressure waveforms generated by the pulmonary artery catheters or monitor pressure-volume loops by conductance catheters in this study.We found that RV diastolic dysfunction is a common feature in patients with CTEPH. Measurements of early diastolic SR and indexed RA area were very helpful in stratifying RV diastolic dysfunction. RV diastolic dysfunction preceded RV systolic dysfunction and might occur earlier before the RA or ventricular filling pressure increase. An increased preoperative indexed RA area might predict a decreased postoperative exercise performance.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The Institutional Review Board of Fuwai Hospital approved the study protocol , and the procedures followed were in accordance with the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.HM collect and analyze data and draft manuscript. WS collect data and follow up the patients. SL perform pulmonary endarterectomy. DH discuss the results and revise this manuscript. L-YW and HL collect echo data. S-sZ, Z-wW, and RR collect clinical data. W-xY collect the patients and treat them at clinics. All authors contributed to the article and approved the submitted version.This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2017-I2M-3-003) and Capital Clinical feature application research and achievements promotion (Z-171100001017215).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.


His bundle pacing (HBP) can be achieved in 2 ways: selective HBP (S-HBP), where the His bundle is captured alone, and nonselective HBP (NS-HBP), where local myocardium is also captured, resulting a pre-excited electrocardiogram appearance.We assessed the impact of this ventricular pre-excitation on left and right ventricular dyssynchrony.We recruited patients who displayed both S-HBP and NS-HBP. We performed noninvasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern.P < .0001). NS-HBP did not prolong RVAT  but did prolong QRS duration . In patients with narrow intrinsic QRS (n = 6), NS-HBP preserved LVAT  but prolonged QRS duration  and mean RVAT  compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP, but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP.Twenty patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5 ms (95% confidence interval: -0.6 to -10.4, noninferiority Compared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dyssynchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients.  S-HBP results in an electrocardiographic appearance of an isoelectric interval between the pacing stimulus and QRS onset  of similar duration to the intrinsic HV interval. In nonselective His bundle pacing (NS-HBP) the local myocardium surrounding the His bundle is captured alongside the His bundle itself. QRS prolongation therefore occurs owing to slow cell-to-cell myocardial conduction during the initial poststimulus period, where there would have been an isoelectric interval in S-HBP.His bundle pacing (HBP) has emerged as a paradigm shift in pacemaker therapy. Conventional ventricular pacing results in slow cell-cell myocardial conduction, resulting in a broad QRS complex.NS-HBP has the potential advantage of providing continuous pacing even if conduction system block develops distal to the pacing site. However, it is not known if the QRS widening seen in NS-HBP occurs only owing to isolated prolongation of right ventricular activation or if it also represents dyssynchronous left ventricular activation, which could have detrimental effects on cardiac function. This has important implications for implantation and programming for HBP.In this study, we used high-resolution noninvasive epicardial mapping to measure the within-patient effect of HBP selectivity on intraventricular electrical synchrony.Patients undergoing HBP were recruited if both S-HBP and NS-HBP were observed in the same individual patient. S-HBP and NS-HBP were defined according to internationally recognized criteria (set out in the Online Appendix).All patients were fitted with a 252-electrode noninvasive epicardial electrical mapping (ECGI) vest  and underwent low-dose thoracic computed tomography for cardiac anatomy and electrode positions. The ECGI methodology has been described and validated in previous work: multielectrode body-surface potentials are combined with radiologically acquired epicardial anatomy using the ECGI solution to the inverse problem to reconstruct unipolar epicardial electrograms. ECGI recordings were made during intrinsic rhythm, S-HBP, and NS-HBP.95) was used to quantify resynchronization.95) was similarly calculated.Activations from individual electrodes were temporally annotated based on the most negative dv/dt (the steepest slope of the voltage-time relationship) and visualized on patients’ 3-dimensional cardiac model. The total left ventricular activation time (LVAT) was calculated from earliest to latest activation. This value can be skewed by outliers caused by noise and anatomical and temporal mis-annotation; therefore the activation time of 95% of activations  implants. These patients had intraprocedural ECGI measurements, and HBP was performed for attempted correction of left bundle branch block (LBBB). These patients were included only when both selective and nonselective HBP both produced correction of LBBB or both failed to produce correction of LBBB. If the femoral route was used, a quadripolar electrophysiology catheter was placed on the bundle of His. If the subclavian route was used, a SelectSecure 3830 lead was delivered via either a C304-His deflectable sheath or C315 fixed curve sheath (leads and delivery system: Medtronic). The lead was not actively fixated unless BVP failed, in which case the SelectSecure 3830 lead was deployed for permanent HBP.The second group of patients had permanent SelectSecure 3830 HBP leads implanted prior to recruitment, for clinical indications. ECGI measurements in these patients were performed at least 6 weeks after implantation.95 by HBP has previously been defined as resynchronization95 that are <10 ms cannot be distinguished from measurement variation. Therefore, the primary analysis was powered with a noninferiority margin of 10 ms LVAT95 prolongation by NS-HBP compared to S-HBP. From previous analysis of HBP LVAT95,95 is statistically noninferior (not prolonged by >10 ms) to S-HBP, 18 patients provide 80% power at the 0.05 significance level. Planned secondary analyses are set out in the Online Appendix. Paired t tests were used for within-patient comparisons. Statistical analyses were performed using the statistical environment “R” with the “ggplot2” visualization package .Greater than 10 ms reduction in LVATTwenty subjects were recruited; their baseline demographics are displayed in 95 from S-HBP to NS-HBP for all 20 patients was -5.5 ms , 95% confidence interval: -0.6 to -10.4 ms, n = 20. NS-HBP LVAT95 was statistically noninferior to S-HBP (noninferiority P < .0001). RVAT95 was also not prolonged by NS-HBP compared to S-HBP but QRSd was on average 22.1 ms longer with NS-HBP compared to S-HBP .In the primary analysis, the mean within-patient change in LVAT95 was not prolonged by NS-HBP compared to S-HBP. NS-HBP produced a mean 16.8 ms increase in RVAT95 compared to S-HBP; this finding did not meet statistical significance . QRSd was significantly prolonged by NS-HBP by an average of 31.4 ms compared to S-HBP in these patients . Example electrocardiograms of S-HBP and NS-HBP are shown in In patients with a narrow intrinsic QRS complex (n = 6), LVATECGI activation maps of S-HBP and NS-HBP demonstrated that left ventricular activation pattern appears unchanged from intrinsic rhythm to S-HBP and to NS-HBP. Right ventricular activation appears unchanged from intrinsic rhythm to S-HBP. NS-HBP, however, displays early activation in the basal right ventricle (RV), consistent with capture of local myocardium alongside the His bundle. Example ECGI activation maps from a patient with narrow intrinsic QRS are shown in Example ECGI epicardial propagation cines from the same patient can be viewed in the accompanying In this study we measured the effects of HBP selectivity on left and right ventricular activation time and pattern using high-resolution epicardial mapping. There were several important findings: (1) NS-HBP preserves left ventricular electrical synchrony, despite prolonging QRS duration, when compared to S-HBP; (2) NS-HBP produces some prolongation of right ventricular activation time compared to S-HBP, which contributes to QRSd prolongation; (3) NS-HBP produces pre-excitation of the basal right ventricular epicardium, contributing to QRSd prolongation, but does not alter left ventricular activation pattern compared to S-HBP.end are criteria for NS-HBP and must result in a longer QRS complex than with S-HBP. The “underlying” QRSd of NS-HBP can be calculated as Stim-QRSend minus HV interval or estimated as the time to QRS offset from the inflection at the junction between the slurred pseudo-delta-wave and the sharp deflection of a normal QRS. However, to exclude NS-HBP QRS prolongation in this way is to assume it has no importance. Large observation analyses suggest that QRS prolongation (whether through RVP or BBB) is associated with worsened ventricular function and higher mortality.In patients with normal, narrow baseline QRS, NS-HBP necessarily entails a degree of QRSd prolongation compared to intrinsic QRS; indeed, it is defined by it: shortening of Stim-V with preservation of Stim-QRSright-sided His bundle and the right-sided His lead electrode would be right ventricular myocardium.left ventricular activation is expected and has been observed.NS-HBP, however, has not been associated with worsened outcomes when compared to S-HBP in observational analysis,95) was increased by NS-HBP in patients with intrinsically narrow QRS complexes. Although this did not reach statistical significance, the sample size for this subgroup analysis (n = 6) was not, a priori, powered for. The mean within-patient increase in RVAT95 was 16.8 ms. Although this is modest compared to HBP resynchronization induced changes in activation time, which can be several times larger,95 reduction in LBBB and this has important clinical effects of reduced mortality and morbidity.95 in the group of all patients, this group includes patients with right bundle branch block (RBBB), in whom NS-HBP is known to produce RV resynchronization,95 dyssynchrony may be confounded by RV resynchronization in these patients. Indeed, there was substantial shortening of RVAT95 in the 2 patients with RBBB (>50 ms) and some shortening in patients with LBBB (>20 ms). An assumption of the model of clinically beneficial preservation of LV synchrony by NS-HBP is that RV dyssynchrony is less important than LV dyssynchrony. This is borne out in observational analysis of patients with heart failure and LBBB suffering worse outcomes than those with RBBBThe point estimate for RV electrical dyssynchrony . Some outliers are expected owing to natural biological and measurement variation, but there is also likely to be a subset of patients with long intrinsic HV intervals in whom left ventricular activation is prolonged by NS-HBP. HV intervals in patients with conduction disease can be very long, including >100 ms (if this is not corrected by HBP). This allows a long period of time for even slow cell-to-cell myocardial propagation to activate a large region of right ventricular myocardium and perhaps break through the septum to activate a large amount of left ventricular myocardium before His-Purkinje activation overtakes. This could be enough to produce important LV dyssynchrony: Patients with accessory pathway–induced pre-excitation, in rare cases, can have dyssynchrony-induced symptoms that resolve with ablation.We do not infer from our results that NS-HBP preserves LVAT95 prolongation seen with NS-HBP with patients with narrow intrinsic QRS complex, for example, may have been statistically significant with a larger sample size. The ECGI methodology has been validated previously but makes several assumptions, including static geometry, and does not image the septum,95 changes have been found to correlate with changes in cardiac output. ECGI is less well studied for assessment of RV dyssynchrony. The assessment of LV synchrony was acute but was consistent with the long-term clinical outcomes observed by Beer and colleagues.The sample size was prospectively powered for the primary analysis, but subgroups were small. The RVATNS-HBP preserves left ventricular electrical synchrony, despite prolonging QRS duration, when compared to S-HBP. NS-HBP can be safely targeted in most patients.10.13039/501100000274British Heart Foundation . Dr Arnold is supported the 10.13039/501100005617BHF Imperial Centre of Research Excellence (RE/18/4/34215) and the NIHR Imperial Biomedical Research Centre.This study was funded by the The authors have no conflicts to disclose.All authors attest they meet the current ICMJE criteria for authorship.All patients gave written, informed consent.The study was approved by the local ethics committee (13/LO/1440). The research reported in this paper adhered to the Helsinki Declaration.