However, exercise capacity did not differ between patients with and without LGE . In adults with Ebstein’s anomaly fibrosis estimated by LGE-CMR was localized in the right atrium and the right ventricle only. Volume overload resulting from tricuspid regurgitation might be a factor conducive to fibrosis. Myocardial fibrosis did not influence exercise capacity. Association between myocardial fibrosis and supraventricular arrhythmia was confirmed.Heart failure and arrhythmia are common complications in adults with Ebstein’s anomaly. They may result not only from hemodynamic alterations, but also from myocardial fibrosis. Late gadolinium enhancement (LGE) by CMR enables the evaluation of myocardial fibrosis. The aim of the study was to asses the presence of LGE and its relation to clinical outcome. We studied a group of 37 unoperated adults aged 43.0 ± 14.4 years with Ebstein’s anomaly from the congenital heart disease outpatient clinic. Study protocol included: cardiopulmonary test, assessment of supraventricular arrhythmia (SVA), and CMR with evaluation of cardiac chambers’ morphology and function, and presence of LGE. Variables following normal distribution were shown as mean ± SD if otherwise median (range) was applied. Fibrosis was found in 18 patients (48.6%) and was distributed as follows: 12 patients (32.4%) in the right atrium, 12 (32.4%) in the atrialized right ventricle, and 2 (5.4%) in the functional right ventricle. In patients with fibrosis, the tricuspid regurgitation fraction was bigger (48.3 ± 19.7 vs. 36.1 ± 22.6%,  Ebstein’s anomaly (EA) is an anomaly comprising 0.5% of all congenital heart diseases (CHD) in adults. This defect is characterized by a displacement of septal and posterior tricuspid leaflets toward the apex of the right ventricle (RV). As a result, the inlet portion of RV creates the “atrialized” part and functions as an atrium, whereas the trabecular part and the outflow tract constitute the functional right ventricle (fRV). These anatomical abnormalities cause a marked dilatation of the right atrium, which additionally may be influenced by a significant tricuspid regurgitation .Despite the altered cardiac hemodynamics, even patients with a severe defect often reach adulthood, although their lifespan is significantly shortened. The cause of 20% of deaths is arrhythmia, whereas 50% of the population dies of heart failure . As has Cardiac magnetic resonance (CMR) is increasingly used to detect pathologic fibrosis and has an expanding role in noninvasive diagnosis of congenital heart diseases. Late gadolinium enhancement (LGE) estimated by CMR allows us to evaluate the presence of myocardial inflammation, fibrosis, and injury. This method is based on relative accumulation of gadolinium under these conditions as the result of slower washout kinetics and the increased extracellular volume. Clinical usefulness of this method has been demonstrated in patients with both ischemic and non-ischemic heart failure , 8. In aThe aim of the study was to assess the presence of myocardial fibrosis with LGE-CMR, and to determine factors leading to this process, its potential impact on exercise capacity and the occurrence of supraventricular arrhythmia in adult patients with Ebstein’s anomaly.A database of grown-up congenital heart disease outpatient clinic of the Department of Cardiology, University of Medical Sciences in Poznan, Poland identified 52 patients with Ebstein’s anomaly. Four of those refused to participate in the study, 5 were excluded due to the previous cardiosurgery, 5 due to implanted pacemakers, and one due to claustrophobia. The remaining 37 patients  formed our study group, aged 18–76 years. Sinus rhythm was present in all of them at the time of examination. Coexisting cardiac anomaly was present in three patients (8.1%): 2 trivial atrial septal defects and 1 mild pulmonary stenosis. The study protocol comprised the following: medical history, clinical examination, laboratory tests, 12-channel ECG, echocardiography, cardiopulmonary exercise test, and CMR.Cardiac magnetic resonance was performed on 1.5 T scanner  with the use of a six-element matrix coil combined with a 2–4 element spinal coil. All images were ECG gated and performed during patient expiration breath hold. Total examination time was 45–55 min. Steady-state free-precession imaging was used for volume assessment of the ventricles and atria. Standard 4- and 2-chamber planes with a stack of short-axis views and contiguous axial slices covering the heart from the RV outflow tract to the diaphragmatic surface of the right ventricle were used. Typical slice thickness was 8 mm without any gap. To fully characterize both, the left and right cardiac chambers the following volumes: left atrium (LA), left ventricle (LV), functional right ventricle (fRV), atrialized right ventricle (aRV), right atrium (RA), and functional right atrium (fRA) calculated as a sum of RA and aRV . Parameters characterizing right-heart chambers were defined according to Yalonetsky et al. . A line Based on previously published studies, tricuspid regurgitation (TR) was considered severe if the regurgitant fraction exceeded 35% .An index originally introduced in echocardiography by Celermajer  for EbstLate gadolinium enhancement was performed 10–15 min after contrast injection . The inversion time was determined for each patient individually for complete nullification of the myocardium signal to accommodate the gradual washout of the contrast agent from the myocardium. A standard turbo flash, breath hold, two-dimensional, T1-weighted inversion recovery sequence with non-selective 180˚ inversion preparation pulse was used. The slice thickness was 8 mm, no gap, pixel size 2 × 1.5 mm, repetition time—793 ms, echo time—3.17 ms, flip angle—25°, matrix—156 × 256. Signal-to-noise ratio (SNR) was measured as a mean signal value of tissue divided by standard deviation of the image background: SNR fib = 33.25 (for fibrous tissue), SNR norm = 10.7 . Contrast-to-noise ratio (CNR) was measured according to the following formula: CNR = SNR fib − SNR norm = 22.55, i.e., SNR of fibrous atrium minus SNR of normal atrium. LGE was performed in 2, 3, and 4 chambers and short-axis planes which also covered both atria. Total LGE was evaluated qualitatively as LGE present/absent and determined by location within fRV, aRV, RA, fRA, LV, and LA , carbon dioxide production (VCO2), and minute ventilation were measured with breath by breath technique using Sensor Medics, model Vmax 29. Peak VO2 was defined as the average for the last 20 s of exercise and expressed as ml/kg/min, as well as the percentage ranges predicted for sex, age, height and weight  or NYHA class II [5 (13.5%)]. Mean blood saturation was 97.6 ± 0.7; no case of saturation below 95% was reported. Detailed demographic and clinical characteristics of the study group are presented in Table Myocardial fibrosis was found in 18 (48.6%) patients with EA, of whom 16 showed LGE in the fRA, 10 had LGE detected in RA as well as in aRV, and only 2 patients had fibrosis detected in the myocardium of fRV. Demographic and clinical characteristics of the study group are presented in Table p = 0.55), and sex . We also showed no significant difference between individuals with and without fibrosis in the severity of Ebstein’s anomaly assessed by the Celermajer index . Among all CMR-derived chamber dimensions, the only significant difference between LGE (+) vs. LGE (−) patients was reported for maximal volumes of atria . The volume of functional RA (aRV + RA) with LGE was significantly greater when compared to the size of atria without LGE . A significant difference in volume was also demonstrated for anatomical RA—its volume was greater in patients with fibrosis . Such a difference was not confirmed when analyzing the aRV volume .Patients with and without LGE did not differ in the demographic data, i.e., age . A box plot . There was no significant difference in the TR fraction observed between all the other subgroups . With regard to specific atrial walls, fibrosis was seen mostly on the posterior wall [14 out of 16 (87.5%)] and on the anterolateral wall [12 out of 16 (75%)]. Septal region was affected only in 4 patients (25%) with atrial LGE.Severe tricuspid regurgitation was present in 26 (60.5%) individuals and regurgitation fraction was significantly greater in patients with myocardial fibrosis  vs. 84.5 (37.5–690.5) ml/m2, p = 0.035]. Such a difference was not confirmed when analyzing the aRV volume .The volume of functional RA in which fibrosis was detected was significantly greater when compared to the size of atria without LGE [351.0 (70.8–1571.4) vs. 279.0 (65.9–456.9) ml/mp = 0.046]. Patients with fibrotic fRA presented SVA more frequently in than those with healthy myocardium , significantly more frequently in those with LGE , and BNP .There were no differences in cardiopulmonary parameters and BNP concentration between patients with and without LGE—peak p = 0.049)  Table .Table 2FOur analysis revealed the presence of late gadolinium enhancement in nearly half of adult patients with Ebstein’s anomaly. Myocardial fibrosis was observed only in the right atrium and right ventricle. In most cases, it was found in the functional right atrium composed of the anatomical right atrium and the atrialized right ventricle. These chambers are characterized by dissimilar histological architecture: in the wall of the anatomical right atrium, the number of cardiomyocytes is lower, whereas the amount of extracellular matrix is greater than in the right ventricle wall . There aAs shown in our study, LGE occurs with the same frequency in the myocardium of the anatomical right atrium as in the atrialized right ventricle. It is, therefore, probable that the dissimilar histological structures of the right atrium and right ventricle do not determine the presence of fibrosis. It seems that it is the volume overload caused by the significant tricuspid regurgitation, which was also confirmed in the majority of our patients, that may be crucial. Another possible mechanism of fibrosis might be a mechanical insult caused directly by a regurgitant jet. However, a clear determination of underlying cause is difficult due to extremely enlarged atria and small group size. In addition, we confirmed that the severity of tricuspid insufficiency is associated with the extent of fibrosis within the functional right atrium. The end-systolic volume of the anatomical right atrium has been proven the only factor increasing the probability of fibrosis in the population studied as well. Nevertheless, there have not been many studies on LGE in the right atrium published. Sato et al.  reportedThe results of our study show that the primary insult, which in Ebstein’s anomaly patients is volume overload, seems to have only little influence on the process of fibrosis of the right ventricle. Contrarily to the atrial walls, LGE was observed within the right chamber only in two patients. Fratz et al. proved in a CMR analysis that tricuspid regurgitation determines the size of fRV. However, their study did not involve the assessment of LGE . Data frAccording to current knowledge, there are several factors that can induce the process of myocardial fibrosis. They include: neurohormonal activation caused by pressure and volume overload , 32), geThe suggestion of the influence of the presence of LGE on exercise capacity was first done by Daliento et al. who demonstrated myocardial fibrosis among EA adults in autopsy examinations . ContrarWhen analyzing the impact of fibrosis on functional status, one must consider the complex pathomechanism of exercise capacity reduction in the Ebstein’s anomaly population. The right atrium, enlarged by the atrialized part of right ventricle, causes a leftward displacement of the intra-ventricular septum. This results in a left ventricular geometry alteration, reducing its inflow and consequently cardiac output. The volume overload of the right ventricle caused by the tricuspid regurgitation is worth noting as well as is the dyssynchrony of the atrialized part which contracts during the atrial diastolic period , 26. NevOur study has proven that supraventricular arrhythmia is significantly more frequent in adults with Ebstein’s anomaly who had myocardial fibrosis confirmed by LGE. This finding is consistent with current knowledge and confirms that supraventricular arrhythmia encountered in Ebstein’s anomaly (except for Wollf–Parkinson–White syndrome resulting from the presence of accessory pathway) is thought to be an effect of enlargement and fibrosis within the functional right atrium . The preOur study had a cross-sectional character and was conducted on a relatively small study group. Its statistical power is, therefore, limited and the multivariate logistic regression analysis to evaluate the strongest factors related to the presence of LGE could not be done. However, other studies involving adults with congenital heart disease have carried out a comparable number of patients.Another limitation of the study was the use of the 2D instead of 3D sequence for the assessment of atrial fibrosis. In most high spatial resolutions, atrial fibrosis is examined by a nonbreath-hold 3D sequence which is considered to be the most accurate and quickest method –43. As oIn adults with Ebstein’s anomaly examined with CMR, late gadolinium enhancement characteristic for myocardial fibrosis was a frequent finding detected only within the right atrium and right ventricle. The volume overload resulting from tricuspid regurgitation might be conducive to the development of fibrosis. Myocardial fibrosis, localized mostly in the atria and not in the ventricles, had no negative impact on exercise capacity. However, we confirmed the association between myocardial fibrosis and supraventricular arrhythmia in this population.


In systemic lupus erythematosus (SLE), cardiac manifestations, e.g. coronary artery disease (CAD) and myocarditis are leading causes of morbidity and mortality. The prevalence of subclinical heart disease in SLE is unknown. We studied whether a comprehensive cardiovascular magnetic resonance (CMR) protocol may be useful for early diagnosis of heart disease in SLE patients without known CAD.In this prospective, observational, cross-sectional study CMR including cine, late gadolinium enhancement (LGE) and stress perfusion sequences, ECG, and blood sampling were performed in 30 consecutive SLE patients without known CAD. All patients fulfilled at least 4/11 American College of Rheumatology (ACR) Criteria for the classification of SLE.30 patients  were enrolled, mean age was 45±14 years and mean SLE disease duration was 10±8 years. 80% had low to moderate disease activity. All had a low SLE damage index. CMR was abnormal in 13/30 (43%), showing LGE in 9/13, stress perfusion deficits in 5/13 and pericardial effusion (PE) in 7/13. Patients with non-ischemic LGE had more often microalbuminuria while patients with stress perfusion deficits a history of hypertension, renal disorder as ACR criterion, repolarisation abnormalities on ECG and larger LV enddiastolic volume index. There was no correlation between clinical symptoms and CMR results.Our study shows that cardiac involvement as observed by CMR is frequent in SLE and not necessarily associated with typical symptoms. CMR may thus help to detect subclinical cardiac involvement, which could lead to earlier treatment. Additionally we identify possible risk factors associated with cardiac involvement. Systemic lupus erythematosus (SLE) is a systemic, autoimmune disease which can affect virtually all organs. CardiacTherefore we studied the diagnostic yield of a comprehensive, routine cardiac magnetic resonance (CMR) examination, including adenosine-stress perfusion and late gadolinium enhancement (LGE) in SLE patients without history of coronary artery disease (CAD).nd or 3rd degree atrioventricular block, trifascicular block, asthma and severe chronic obstructive pulmonary disease. Patients were recruited consecutively between 2010 and 2014 at the University Hospital Basel in collaboration with the Divisions of Rheumatology and Immunology and the Swiss SLE Cohort Study (SSCS)[In this prospective, observational, cross-sectional study we included a total of 30 consecutive patients with the diagnosis of SLE as defined by the American College of Rheumatology (ACR) Classification Criteria. Exclusidy (SSCS). The stuCase history, SLE disease duration, disease activity as well as SLE disease related organ damage and recent medication were provided by the treating physician after a routine outpatient visit or during inpatient hospitalisation. For the evaluation of SLE disease activity the European Consensus Lupus Activity Measurement (ECLAM) score (ranging from 0 indicating no activity to 16.5 as maximum) and the Physician’s Assessment of Disease Activity  were used. For SLEAt the day of the CMR, a cardiologist obtained a detailed cardiovascular history and a clinical exam was performed. For the classification of chest symptoms we chose the definition of angina pectoris by the European Society of Cardiology . AccordiAdditionally an ECG and laboratory investigations were done (including high-sensitivity troponin and brain natriuretic peptide). ECGs were interpreted by an experienced cardiologist . Repolarisation abnormalities were defined as ST-segment elevation, depression or discordant T-wave inversions.Patients underwent routine CMR including perfusion studies at stress and rest as well as LGE sequences in a mean time frame of 23 days  before or after the index visit with their treating physician.Routine ECG-gated CMR studies were performed in the supine position on a 1.5 Tesla magnet  equipped with phased array body coils for signal reception using commercially available cardiac software. Heart rate and ECG were continuously monitored, blood pressure every two minutes. The stress test to evaluate ischemia was performed by infusion of 140 μg/kg/min adenosine. After 3 minutes of adenosine, acquisition of breath-hold saturation recovery gradient recalled echo (SR-GRE) images and injection of contrast media were started simultaneously. Adenosine infusion was stopped upon completion of stress perfusion MR. Rest perfusion images were acquired without adenosine but otherwise with identical contrast material settings and sequence parameters as mentioned before for stress. Cine images for functional assessment were acquired with ECG gated 2D steady state free precession (cineTrueFisp) in a stack of short axis, 2-chamber and 4-chamber views. For late enhancement images inversion recovery turbo fast low angle shot (IR-tFLASH) images were acquired ~15 min after a cumulative dose of 0.2 mmol/kg GdDOTA in the short axis, 2-chamber and 4-chamber views. The inversion time was optimized in order to obtain null signal from normal myocardium. CMR analyses were performed off-line by experienced readers. Regional wall motion, perfusion and late gadolinium enhancement were interpreted by consensus reading of an experienced cardiologist  and an experienced radiologist (JB).Abnormal CMR was defined as presence of LGE (ischemic or non-ischemic pattern), signs of stress-perfusion deficit indicating ischemia or pericardial effusion (PE). Pericardial effusion was visually categorized by consensus reading to . As LV and right ventricular (RV) functional parameters, LV ejection fraction (LVEF) and RV ejection fraction (RVEF) were calculated quantitatively. Normal LVEF was defined as >54%, normal RVEF as >45%. LV mass, LV enddiastolic volume, LV stroke volume as well as RV enddiastolic volume were calculated and indexed on body surface area.Categoric variables are expressed as counts (percentage). Continuous variables are expressed as mean ± standard deviation (SD) if normally distributed, or as median and interquartile range if not normally distributed. Comparisons were performed using Student’s t-test, Mann—Whitney U-test or Pearson chi-square test, as appropriate. A p-value of <0.05 was considered statistically significant, significance levels are two-tailed, and confidence intervals (CI) are 95%-CI. All calculations were done with the use of the SPSS statistical package version 22.0 .In all we screened 51 patients for participation in the study. 20 patients were excluded prior to CMR . One patient discontinued CMR after localizer sequences due to claustrophobia and was thus excluded from the analysis. Two patients did not receive adenosine stress testing since they had normal coronary artery status in a recent coronary angiography and refused additional stress testing, resulting in 28 patients with adenosine stress testing. Baseline characteristics of the final cohort of 30 patients are shown in CMR was interpreted as abnormal in a total of 13 patients (43.3%). An overview of the observed abnormalities is given in 2, mean left ventricular enddiastolic volume index (LVEDVi) 77±15 ml/m2. The LVEF of the above-mentioned patient was slightly reduced to 53% and CMR showed additionally LGE of a non-coronary pattern, regional wall motion abnormalities and a stress perfusion deficit. RVEF was normal in all patients (mean RVEF 61±8%).In functional imaging all except one patient had normal LVEF (mean LVEF 68±6%). Mean left ventricular mass index (LVMi) was 51±14 g/mRegarding the 13 patients with abnormal CMR, there were different combinations of CMR findings observed with 6/13 patients showing one structural or functional abnormality, 6/13 patients showing combination of two abnormalities and 1/13 patients showing three abnormalities. Frequency of the observed structural abnormalities and combinations are shown in In one patient with stress-perfusion deficit coronary angiography was performed showing significant coronary two-vessel disease .Patients with LGE had microalbuminuria more frequently than patients without LGE , p = 0.048). There were no other significant differences with regard to SLE manifestations, the above-mentioned baseline characteristics or functional CMR results. Details are provided in Stress-perfusion deficits were found in five of 28 patients with adenosine-stress perfusion imaging. Comparing patients with versus without stress-perfusion deficit, there were significant differences regarding hypertension as cardiovascular risk factors, presence of renal disorder as ACR criterion for the classification of SLE, repolarisation abnormalities on ECG, brain-natriuretic peptide and functional left ventricular CMR parameters see . There wTo our knowledge, this is the first study using a comprehensive, routine cardiac magnetic resonance (CMR) examination including functional assessment, adenosine stress-perfusion imaging and late gadolinium enhancement to evaluate cardiac involvement in oligosymptomatic SLE patients without known coronary artery disease.The current study showed, that in more than 40% of patients CMR yielded abnormal findings including pericardial effusion, LGE of a non-ischemic pattern or stress-perfusion deficits. Most frequently we observed non-ischemic LGE and PE but in 20% of patients we found adenosine-stress perfusion deficits as sign of coronary artery disease. In more than half of the SLE patients with abnormal CMR we found a combination of two or more structural or functional abnormalities.Previous studies reporting the use of CMR in SLE patients focused on either myocardial tissue characterisation or on myocardial perfusion, but there was a lack of data on the combination of both techniques in the same patient cohort.In the first CMR case-series and studies in SLE patients, myocardial tissue characterisation was usually performed by rather investigational and non-fully standardised techniques such as earlier forms of T1- or T2-mapping. In these studies myocardial signal alterations were found in subsets of SLE patients and were inconsistently related to SLE disease activity, but no LGE imaging was used –19. In oAdenosine-stress perfusion CMR imaging was studied previously in 22 SLE patients with typical or atypical chest pain in the absence of prior obstructive coronary artery disease evaluated by means of coronary computed tomography angiography . PrevaleOn functional CMR analysis LV enddiastolic volume index was larger.LGE identifies increased interstitial volume e.g. caused by myocardial oedema due to acute or chronic inflammation as well as focal fibrosis and scar tissue –31. LGE Coronary artery disease is a leading cause of morbidity and mortality in SLE patients and there is an unmet need to identify SLE patients with the highest risk of cardiovascular adverse events early in disease course. In our study repolarisation abnormalities, hypertension, renal disorder as ACR criterion and larger LV enddiastolic volumes were more often observed in patients with stress-perfusion deficits. Additionally reduced myocardial perfusion may be related to secondary peripheral Raynaud’s phenomenon a clinical phenomenon not included in our study . Since cAn algorithm for the cardiovascular work-up of SLE patients was recently proposed together with a systematic review by Mavrogeni et al.. In thisSome limitations, however, need to be mentioned. The current study–although being prospective—was an observational, cross-sectional study in a single center with a limited number of patients especially with regard to statistical considerations and calculations. Between group comparisons should be interpreted with caution, but may help to guide further research. Since 83% of our patients were participants of the Swiss SLE Cohort Study, we had a high quality of baseline documentation regarding clinical SLE parameters.In some patients with stress perfusion deficits, we have no final diagnosis of CAD since coronary angiography or coronary computed tomography was not performed in all patients–but it is known that with a comprehensive CMR approach combining stress-perfusion and LGE, sensitivity and specificity for CAD diagnosis is 89% and 87% respectively .For CMR acquisition we used a comprehensive routine CMR protocol which can be easily applied, but we did not use newer techniques like T1, T2, T2* and extracellular volume mapping which have recently been recommended by a consensus statement by the Society for Cardiovascular Magnetic Resonance and the European Association for Cardiovascular Imaging–especially in the context of the evaluation of suspected myocarditis and myocardial disease . This waCardiac involvement as demonstrated by CMR is frequently observed (43.3%) in SLE patients without typical cardiac symptoms, so there is a need of thorough investigation of cardiovascular disease in this patient group. CMR therefore may help to detect subclinical cardiac involvement particularly in patients with repolarisation abnormalities on ECG, hypertension or renal disorder and should be preferred as first line non-invasive cardiac imaging modality when available. The prognostic impact of LGE and stress-perfusion deficits on CMR remains to be determined. Further studies should additionally implement newer CMR sequences and cardiac CT in SLE with stress perfusion abnormalities that are compatible with coronary artery disease.


High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues  of explanted hearts. Respiration rates were comparable in ventricular samples of heart failure patients obtained during open heart surgery by standard tissue preparation or ex vivo endomyocardial biopsy , and the mitochondrial oxidative capacity in samples from these patients remained stable for 8 h when stored in either of two common preservation buffers. The oxidative capacity was 44% lower in heart failure than in transplant recipients  and correlated positively with heart function . High-resolution respirometry of ventricular tissue is feasible in transcatheter biopsies, facilitating clinical studies on myocardial mitochondrial function in patients not undergoing heart surgery.The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation  was significantly higher than in the upper heart chambers (atria). Moreover, they found that mitochondrial oxidative capacity was reduced by 44% in heart muscle biopsies from patients with heart failure compared with biopsies from heart transplant recipients with normal ventricular function. Stimulating the respiration rate of mitochondria in ventricular heart cells could be a promising strategy for improving cardiac function. Due to the aging of the population and improved survival from acute cardiac diseases, HF prevalence is increasing steadily, with a 20% lifetime risk for the development of HF2, which has a poor prognosis. The pathophysiology of HF is complex, but growing evidence from both preclinical and clinical studies points to impaired mitochondrial function in HF4. Thus, mitochondria appear to be a promising therapeutic target to improve cardiac function5.Heart failure (HF) is a rising medical and societal burden8. Polarographic measurement of ex vivo mitochondrial oxygen consumption in the presence of specific substrates has been widely accepted as the gold-standard method for analyzing mitochondrial oxidative capacity and efficiency in human tissue samples, i.e., skeletal muscle and the liver13. Thus far, assessment of ex vivo cardiac mitochondrial respiration has been limited to samples acquired during open heart surgery, which precludes follow-up measures during clinical trials and restricts patient groups. Of note, the mitochondrial oxidative capacity of left ventricular (LV) tissue obtained during open heart surgery was decreased by 40% in terminal HF patients compared to patients with an LV ejection fraction >45%14.Current in vivo noninvasive measurement of heart energy metabolism relies on the relative concentrations of phosphorous metabolites and is restricted to selected clinical centers15. However, EMB has not yet been employed to assess mitochondrial function.Human transcatheter endomyocardial biopsies (EMBs) of the interventricular septum (IVS) are routinely applied for the management of cardiovascular diseases according to the latest scientific statement of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology17, referred to as the “control group”, while analyses of ventricle tissue were mostly applied to patients with end-stage HF following heart transplantation or left ventricular assist device (LVAD) surgery18. Meanwhile, accumulated evidence suggests that the atrial mitochondrial oxidative capacity does not reflect that of ventricular tissue; thus, comparisons of different patient groups must address corresponding heart areas18. Moreover, the use of mitochondrial preservation medium19 or standard tissue perfusion solution17, as well as the storage time until mitochondrial respiration analysis, might also affect respiration rates. Taken together, standardized procedures applicable to clinical trials in larger cohorts are warranted.A number of studies analyzed atrial tissue in patients undergoing valve replacement or coronary artery bypass surgeryTo this end, we analyzed mitochondrial respiration in right atrial, LV, and IVS tissue specimens from heart explants. We then established high-resolution respirometry (HRR) in human transcatheter EMB of the IVS. We tested for the impact of the time lag between tissue acquisition and the start of the experiment and the effect of different preservation media on respiration measurements. Finally, we tested the clinical applicability in a cohort of heart transplant recipients with normal LV function and in patients with terminal HF and related mitochondrial respiration rates to heart function.This registered clinical trial protocol was approved by the ethics board of the university hospital of the Heinrich-Heine University Düsseldorf . All procedures conformed to the World Medical Association Declaration of Helsinki. Before inclusion, all participants gave written informed consent.n = 40), tissue specimens were obtained surgically during LVAD implantation (n = 28) or heart explantation (n = 12). In stable heart transplant recipients with a normal LV function , tissue specimens were obtained during routine surveillance EMB  or ice-cold CUSTODIOL® perfusion solution containing [in mM] 15 sodium chloride, 9.0 potassium chloride, 1 potassium hydrogen 2-ketoglutarate, 4.0 magnesium chloride, 18.0 histidine HCl, 180.0 histidine, 2.0 tryptophan, 30.0 mannitol, and 0.015 calcium chloride in sterile water. Samples were transferred to the laboratory in ice-cold buffer within a few minutes. Part of the ventricular tissue was directly prepared for HRR. The remaining tissue was kept on ice in BIOPS or CUSTODIOL® for 3 or 8 h to assess the impact of storage buffer and time on respirometry. To assess the impact of sample size and tissue acquisition technique on mitochondrial respiration, we harvested EMBs ex vivo using an EMB bioptome from tissue samples of eight patients obtained during LVAD surgery and compared the mitochondrial respiration in these EMBs to that in standard preparations of tissue specimens of the same patients using scissors and forceps.During LVAD surgery, the part of the cardiac apex that corresponds to the LV was excised  for 30 min, and then washed in respiration medium 22. Thereafter, tissue specimens were blotted on filter paper, weighed, and transferred to oxygraph chambers containing 2.3 ml MiRO5. Respiration was measured at 37 °C at oxygen concentrations between 120 and 450 µM in duplicate and analyzed using Datlab software . Oxygen fluxes represent basal or substrate-saturated respiration before adding ADP, ADP-stimulated coupled respiration with octanoyl-carnitine, glutamate, and succinate (state III), and maximal uncoupled respiration after adding the uncoupling factor fccp (state u)23. The oxidative capacity of the mitochondrial oxidative phosphorylation system (OXPHOS capacity) was derived from state III respiration after addition of octanoyl-carnitine, glutamate, and succinate. Mitochondrial leak respiration (state 4o) was induced through inhibition of the enzyme ATP synthase by adding oligomycin12. The respiratory control ratio (state III/state 4o) and the leak control ratio (state 4o/state u) were calculated as surrogate markers of mitochondrial coupling efficiency12. The integrity of the outer mitochondrial membrane was analyzed via exogenous stimulation of state III respiration by cytochrome c24. A stimulation of oxygen flux less than 10% after cytochrome c addition is considered to indicate a preserved outer mitochondrial membrane24.Myocardial mitochondrial respiration in permeabilized myocardial muscle fibers and isolated mitochondria was analyzed ex vivo using HRR following procedures previously established and/or developed for skeletal muscle and liver tissue 26. In short, CSA was measured spectrophotometrically in lysed cells at a 412 nm wavelength after addition of 10 mM dithionitrobenzoic acid, 30 mM acetyl-CoA, and 10 mM oxaloacetic acid. The results have been normalized to the protein content measured colorimetrically via bicinchoninic acid assay.The mitochondrial content was assessed from the citrate synthase activity (CSA) as described previously26. An aliquot of tissue sample prepared for the HRR measurements was transferred to oxygraph chambers containing 2.3 ml MiR5 with 10 mM of the extrinsic fluorophore Amplex red  and horseradish peroxidase 27. Catalyzed by horseradish peroxidase, Amplex red, and hydrogen peroxide produce the red fluorescent compound resorufin (excitation wavelength 563 nm and emission 587 nm). The change of the emitted fluorescence intensity during stepwise addition of the mitochondrial substrates malate and succinate is directly proportional to the production of hydrogen peroxide28. Calibrations were performed with a standard hydrogen peroxide addition.Fluoroscopic measurements of mitochondrial hydrogen peroxide release were performed using an Oxygraph-2k combined with the Fluorescence-Sensor Green of the O2k-Fluo LED2-Module for hydrogen peroxide 9. Oxygraph measurements of isolated mitochondria were performed following the same protocol as for permeabilized fibers, but in a different respiration buffer  at saturating oxygen levels.Mitochondria were isolated by differential centrifugation as described previously29. The cardiac index was calculated using a modified Fick method during right heart catheterization at the time of EMB or at the time of evaluation for heart transplantation and/or LVAD implantation30.The LV ejection fraction was analyzed using the modified biplane Simpson’s rule according to current European Society of Cardiology HF guidelines with a Philips HD15 ultrasound system 9.Relative quantification of myocardial messenger ribonucleic acid (mRNA) expression of genes related to mitochondrial respiratory chain complex I (NDUFS1) and an important mitochondrial transport enzyme, carnitine palmitoyltransferase 1B (CPT1B), was assessed with real-time PCR  and the comparative threshold cycle method (DDCt) with 18S ribosomal RNA as the reference gene, as described previously, in tissue specimens of a small subset of HF patients undergoing LVAD surgery and heart transplant recipients undergoing EMBP-values ≤0.05 were considered significant. Data were analyzed using the paired or unpaired Student's t-test, two-way analysis of variance (ANOVA), and the Sidak post hoc test. Datasets with no Gaussian distribution were analyzed using the Mann–Whitney U test. To test for a linear association between two variables, we used Pearson or Spearman correlation models and partial correlation, depending on whether data were normally distributed.Statistical analyses were performed using Prism 7  and SPSS . Data are expressed as the means ± standard deviation or means ± standard error of the mean. The distribution of age, sex, and body mass index was comparable in HF patients and heart transplant (HTX) recipients Table . Table 1p < 0.01). After addition of the citrate cycle-derived substrates glutamate and succinate, mitochondrial respiration in ventricular samples was approximately 90% higher    Fig. . The unc01) Fig. . CSA was01) Fig. . The res01) Fig. .Fig. 2Cor = 0.9988, p < 0.0001) .There was a strong correlation between oxygen fluxes measured in EMBs harvested using a bioptome from ventricular apex tissue samples obtained during LVAD surgery of HF patients and fluxes measured after standard tissue preparation for the same tissues (01) Fig. . In tiss® preservation buffer. These measurements displayed stable oxygen flux rates for each timepoint and buffer in mitochondrial state III respiration on solely octanoyl-carnitine and the citrate cycle-derived substrates glutamate and succinate plus octanoyl-carnitine, with no effect on uncoupled respiration or the respiratory control ratio   higher and, after addition of the citrate cycle-derived substrates glutamate and succinate, 38%  higher compared to LV tissue specimens of HF patients obtained during open heart surgery  .Based on the above-mentioned experiments, the mitochondrial respiration in LV and IVS tissue specimens is comparable. In EMBs endoscopically harvested from the IVS of heart transplant recipients with a normal LV function, state III mitochondrial respiration on the medium-chain fatty acid octanoyl-carnitine was 44%  Fig. , even afp < 0.0001) and CPT1B  mRNA was significantly reduced in LV tissue specimens of HF patients undergoing LVAD surgery compared to IVS EMBs of HTX patients with a normal LV function 17 or did not focus on differences in mitochondrial respiration between IVS and LV tissue specimens.18 To the best of our knowledge, this is the first study analyzing regional differences in mitochondrial respiration for a significant number of cases (n = 9–11). Increased ventricular OXPHOS capacity compared to atrial tissues might relate to higher mitochondrial content, as suggested by CSA measurements, but calculation of the respiratory control ratio and leak control ratio as surrogate markers of mitochondrial coupling efficiency12 suggests qualitative differences in mitochondrial respiration between ventricular and atrial tissues.Analysis of state III myocardial respiration in LV, IVS, and right atrial tissue specimens obtained from explant hearts of HF patients revealed increased mitochondrial oxygen flux in ventricular compared to atrial tissue specimens. The ventricular OXPHOS capacity in our study was two-fold higher compared to atrial tissues, in line with previous results showing a factor of 2.3 between atrial and ventricular tissues in explant hearts of patients suffering from ischemic or dilated cardiomyopathyc addition resulted in no relevant increase in O2 flux in all measurements, indicating outer mitochondrial membrane integrity33. In contrast to earlier studies, where fiber bundles from 4–6 mg22 to 10–40 mg17 were obtained during heart transplantation18, LVAD, or heart valve surgery34, EMBs taken by a bioptome in our study had a tissue weight of at most 0.5–2 mg. These results suggest that the mechanical stress exerted by a bioptome and differences in tissue weight do not impact oxygen flux measurements compared to standard tissue preparation. To the best of our knowledge, this is the first study analyzing gold-standard myocardial mitochondrial oxidative phosphorylation in bioptome-harvested ventricular EMBs from humans. This facilitates the possibility of including samples from patients in mitochondrial respiration analysis that would not be accessible by a surgical approach. These patients comprise all patients with a clinical indication for EMB. According to the latest scientific statements of the American Heart Association, the American College of Cardiology, the European Society of Cardiology and the International Society for Heart and Lung Transplantation, these include especially patients with new onset of HF with hemodynamic compromise, HF patients with an unexplained restrictive cardiomyopathy, and heart transplant recipients undergoing routine surveillance EMB to test for heart transplant rejection35. Especially in heart transplant recipients, scheduled follow-up EMB facilitates the possibility of longitudinal analysis of myocardial mitochondrial respiration under various clinical influences. Consequently, a great number of patients with various pathologies are becoming accessible for HRR analysis, providing the opportunity for a deeper understanding of myocardial mitochondrial energy metabolism.We analyzed mitochondrial respiration in myocardial samples excised by a scalpel compared to biopsies harvested from the same sample using an endomyocardial bioptome. Both tissue acquisition techniques revealed equal oxygen flux rates. Cytochrome ®, independent of cold storage time up to 8 h. This corresponds to findings in surgically assessed human heart samples showing no changes in respiratory parameters during the first 9 h of tissue preservation before membrane defects occurred17. Cardioplegic solutions and BIOPS have previously been used as a storage buffer in studies analyzing myocardial mitochondrial function36, but to the best of our knowledge, there are no studies comparing mitochondrial respiration after storage in different solutions. We compared the mitochondrial preservation abilities of BIOPS with CUSTODIOL®, an organ preservation solution frequently used for heart transplantation in Europe38. While respiratory parameters were similar, the mitochondrial peroxide release increased after 8 h of CUSTODIOL® storage compared to BIOPS at all time points. This comparison demonstrates the comparability of different study protocols and buffers used in previous studies and suggests the preferential usage of BIOPS for tissue preservation, especially if a delay in measurement initiation is expected and ROS formation is analyzed.To analyze the impact of the cold storage time and preservation buffer on heart energy metabolism, we assessed respiration and ROS production in tissue specimens obtained during LVAD surgery. The mitochondrial state III respiration on fatty acids and citrate cycle-derived substrates, maximal uncoupled respiration, and coupling efficiency were comparable for the two most widely used preservation media, BIOPS and CUSTODIOL16, LVAD vs. valvular surgery34, and failing explant vs. donor hearts18, we not only detected differences in mitochondrial energy metabolism between HF and control patients but also, for the first time, were able to show a significant correlation of mitochondrial respiration and CI measurement, highlighting a direct and close link of energy metabolism to cardiac function. This correlation over a large number of patients remained significant, even after correction for HbA1c serum concentrations, underlining the profound connection of mitochondrial respiration and CI, considering that there is some evidence for impaired mitochondrial respiration in myocardial tissue specimens of patients suffering from type 2 diabetes mellitus39.The mitochondrial OXPHOS capacity in terminal HF patients was reduced 44% compared to HTX recipients with a normal LV function. In contrast to previous studies comparing mitochondrial respiration in surgically obtained tissue specimens of patients with coronary vs. valvular heart disease14. In contrast, analysis of myocardial mitochondrial respiration in isolated mitochondria from LV tissue specimens revealed no differences in OXPHOS capacity between terminal HF and control patients36, possibly indicating that the intrinsic mitochondrial capacity is not affected.Our results support previous data showing 40% diminished OXPHOS capacity in LV tissue specimens of patients undergoing LVAD surgery compared to LV tissue specimens of control individuals with good LV function undergoing cardiac valve surgery40. Additionally, nonfailing explant hearts from patients undergoing combined heart-lung transplantation following severe pulmonary hypertension experience pressure overload and thus do not correspond to healthy hearts. Donor hearts that were not eligible for transplantation or could not be allocated also have limitations for use as controls, as these organs have a long cold ischemia time that affects transplant integrity41. Therefore, defining an adequate control group is one of the main limitations in analyzing human heart tissue. Here, we established HRR for the analysis of mitochondrial respiration in endoscopically harvested EMBs. Analyzing EMBs enables us to obtain tissue specimens independent of cardiac surgery and increase case numbers for a better understanding of mitochondrial respiration in HF pathophysiology.A major challenge of studies analyzing human myocardial mitochondrial respiration in terminal HF is the comparison of pathologic findings with an appropriate control group. It is well known that pressure and volume overload impact myocardial oxygen consumption and energy metabolism; thus, patients with valvular heart surgery might not serve as an adequate control group for patients suffering from HF42. Information on mitochondrial biogenesis in human HF conflicts with the murine results. The amount of mRNA for subunits of the mitochondrial electron transfer chain is normal in explanted failing hearts compared with donor hearts43. Our results support an HF-associated decline in the expression of genes associated with mitochondrial respiration. Further studies focusing on gene expression are needed to address this issue.In a murine model of induced HF, decreased expression of genes related to mitochondrial biogenesis, e.g., PGC-1α, has been shownAccording to previous studies in the field, defining a control group is challenging. We compared energy metabolism in terminal HF patients with HTX recipients. These patients were characterized by a normal cardiac index and no signs of allograft rejection but received an immunosuppressive therapy whose impact on mitochondrial OXPHOS capacity is unknown. However, our correlation of cardiac index measurements with myocardial OXPHOS capacity showed robust results over all patients, as well as within the HF or post-HTX group.In this study, we established HRR as a gold-standard method for the analysis of mitochondrial respiration in human EMB. We detected local differences in mitochondrial respiration, with markedly increased oxidative capacity in ventricular compared to atrial tissue specimens. HRR measurements generated robust results even after prolonged cold storage. Application of this technique in a clinical setting showed a 44% reduced myocardial OXPHOS capacity in HF compared to HTX patients, with a positive correlation of mitochondrial oxygen respiration to cardiac function. This technique will facilitate evaluation of mitochondrial energy metabolism in various patient cohorts, helping to decipher the pathophysiological impact of a disturbed myocardial energy metabolism on HF.Supplementary Table 1Supplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Figure 4


We sought to investigate the association between echocardiographic optimisation and ventricular activation time in cardiac resynchronisation therapy (CRT) patients, obtained through the use of electrocardiographic mapping (ECM). We hypothesised that echocardiographic optimisation of the pacing delay between the atrial and ventricular leads—atrioventricular delay (AVD)—and the delay between ventricular leads—interventricular pacing interval (VVD)—would correlate with reductions in ventricular activation time.  Optimisation of AVD and VVD may improve CRT patient outcome. Optimal delays are currently set based on echocardiographic indices; however, acute studies have found that reductions in bulk ventricular activation time correlate with improvements in acute haemodynamic performance. 10-90) were calculated to identify the optimal AVD and VVD timings that gave the minimal TVaT and VaT10-90 values. We correlated cardiac output with these electrical timings.  Twenty-one patients with established CRT criteria were recruited. After implantation, patients underwent echo-guided optimisation of the AVD and VVD. During this procedure, the participants also underwent noninvasive ECM. ECM maps were constructed for each AVD and VVD. ECM maps were analysed offline. Total ventricular activation time (TVaT) and a ventricular activation time index (VaT10-90 and TVaT). Instead, bulk activation times were reduced by a further 20% when optimised with ECM. A significant inverse correlation was identified between reductions in bulk ventricular activation time and improvements in LVOT VTI (p < 0.001), suggesting that improved ventricular haemodynamics are a sequelae of more rapid ventricular activation.  Echocardiographic programming optimisation was not associated with the greatest reductions in biventricular activation time (VaT EAM-guided programming optimisation may achieve superior fusion of activation wave fronts leading to improvements in CRT response. Cardiac resynchronisation therapy (CRT) is recommended for patients with systolic heart failure, prolonged QRS duration, and left bundle branch block , 2. Desp10-90 Index). The cumulative rate of LV activation appears critical, a finding consistent with previous modelling studies [CRT aims at eliminating the dyssynchrony, which results from bundle branch block activation, by reducing the left ventricular activation time (LVaT) and restoring the mechanoenergetic efficiency of the heart. Rapid LV activation is preferred and is associated with improvements in functional class and symptoms , 10. Soh studies , 12.CRT programming aims at resynchronising the electrical activity to ensure the optimal fusion of all activation wave fronts: intrinsic right ventricular depolarisation, RV paced activation, and LV depolarisation . PatientThe close relationship between activation wave fusion and AHR suggests that the use of electrical indices for CRT optimisation would be beneficial. The recent availability of noninvasive electrocardiographic mapping (ECM) means detailed, patient-specific biventricular activation can now be calculated noninvasively , 18.We sought to investigate the association between echocardiographic optimisation and ventricular activation time, obtained through the use of ECM. We hypothesised that echocardiographic optimisation of AVD and VVD would correlate with reductions ventricular activation time.NCT01831518). We aimed at recruiting 20 patients within 18 months, and the first patient was recruited in September 2014 and the last patient in November 2015. In total, 21 patients were selected on the basis of fulfilling the criteria for CRT implantation: NYHA Class II–IV; echocardiographic Left Ventricular Ejection Fraction (LVEF) < 35%; QRS duration > 120 ms (independently of the QRS morphology); and optimal medical therapy (OMT) for heart failure. The aetiology of heart failure was classified as ischaemic if there was substantial coronary artery disease or history of myocardial infarction or revascularisation and as nonischaemic if none of these were present. Intraventricular conduction disturbances were defined according to AHA/ACCF/HRS Recommendations for the Standardisation and Interpretation of the Electrocardiogram [We undertook a prospective study recruiting consecutive heart failure (HF) patients indicated for CRT-pacemaker (CRT-P) or CRT-defibrillator (CRT-D) at St Thomas' Hospital, London. The study conformed to the principles outlined in the Declaration of Helsinki on research in human subjects. All patients gave written informed consent to participate in the study, which was approved by the Research Ethics Committee , and the echocardiographic optimal AVD was calculated using an iterative method based on the maximal separation of E and A waves recorded by pulsed-wave Doppler of diastolic mitral inflow and the maximal mitral velocity-time integral (VTI), as previously described , 20. The10-90 is the time delay between the 10th and 90th percentiles of activation.During AVD and VVD optimisation, patients underwent ECM using a CardioInsight ECSYNC system  to noninvasively record biventricular epicardial ventricular electrograms and construct 3D isochrone and isopotential activation maps. The key component of the ECM system is a vest embedded with 252 electrodes that is fitted to the patient's torso. ECM maps were constructed on a beat-by-beat basis for the different AVD and VVD tested. After optimisation and acquisition of vest electrograms under each configuration, the participants, with the vest still in position, underwent a thoracic computed tomographic (CT) scan to determine the precise anatomic relation between the cardiac geometry and the torso electrodes, which was used to reconstruct approximately 1500 unipolar electrograms on the epicardial surface of the heart. Based on each data set obtained with the ECSYNC, an activation map of both ventricles was generated offline by animating the activation waveform on the patient-specific CT-derived epicardial surface. Ventricular activation times were calculated from the onset of the QRS to the maximal negative slope of each electrogram and combined for the construction of 3D epicardial isochrone maps. The propagation of depolarisation was evident from the 3D epicardial isochrone maps . SubsequU test, ANOVA, and Kruskal–Wallis test. Post hoc comparisons were performed using Tukey's HSD. Correlations were assessed by the Pearson correlation test. p values less than 0.05 were deemed statistically significant.Statistical analyses were performed using PASW Statistics 21 . Changes in ventricular activation times were compared using the Mann–Whitney The characteristics of the 21 patients are shown in p=0.98) or VaT10-90 index (p=0.701) between the different AVD values tested across the cohort, suggesting that no single AVD was optimal for electrically synchronizing all patients. The shortest VaT10-90 index was seen with AVD 100 ms (62 ± 20 ms), and longer VaT10-90 index values were observed with longer AVDs, especially with AVD 200 ms (VaT10-90 index 81 ± 21 ms). In contrast, the shortest AVD tested (AVD 60 ms) gave the longest TVaT (147 ± 26). The optimal AVD found with echocardiographic optimisation did not correspond to the shortest ventricular times observed. The average VaT10-90 and TVaT values were 21% and 20% lower, respectively, than the optimal AVD found through the iterative method (p=0.368), this is in part explained by the potential for large variability in beat-to-beat and test-retest measurement of LVOT VTI [The effects of varying AVD on ventricular activation time are shown in e method . Whilst LVOT VTI .10-90 index (40%) (Echocardiographic CRT optimisation consistently failed to achieve the greatest reduction in ventricular activation . Two groex (40%) .10-90 index. LV15 appeared to offer the highest LVOT VTI and the shortest VaT10-90 index and TVaT. No single VVD achieved significant reductions in ventricular activation time when plotted for each patient  and between LVOT VTI and TVaT  (The effects of each applied VVD on ventricular activation times and LVOT VTI are shown in  patient . A negat< 0.001)  was obse10-90 and TVaT). Instead, bulk activation times were reduced by a further 20% when optimised with ECM.Echocardiographic programming optimisation was not associated with the greatest reductions in biventricular activation time (VaTp < 0.001), suggesting that improved ventricular haemodynamics are a sequelae of more rapid ventricular activation.A significant inverse correlation was identified between reductions in bulk ventricular activation time and improvements in LVOT VTI (We assessed if the optimal parameters obtained through echocardiographic CRT optimisation rendered similar AVD and VVD timings as assessed by ECM. The main findings of this study were as follows:In keeping with previous studies, we identified that echocardiographic optimisation and ECM optimisation were patient-specific. However, ventricular activation was consistently more rapid when optimised via ECM than when echocardiographic optimisation was performed. These findings appear to suggest that programming changes which improve mitral inflow and left ventricular filling do not necessarily achieve a reduction in total ventricular activation time raising the question as to whether AVD should be set to achieve optimal filling, optimal electrical synchrony, or potentially a combination of the two.LVOT VTI is widely accepted as an echocardiographic parameter positively correlated with both stroke volume and cardiac output . PreviouOur findings suggest that when looking to optimise CRT programming, a strategy of aiming at minimising ventricular activation is associated with significant improvements in LVOT VTI. In addition, this approach is associated with a greater degree of electrical resynchronisation than is typically achieved using echo-guided programming optimisation. Our results also indicate that optimal electrical resynchronisation is associated with the best cardiac output.The main limitation of our study is the relatively small cohort of patients included at a single centre. Risk factors and multifactorial diseases affect clinical response to CRT , 27 and Dp/Dtmax, have previously been correlated with enhanced long term response [Whilst improvements in AHR, measured using response  this mea10-90 activation times amongst both echocardiographically and electrically optimised patients. One explanation could be the degree of scar or fibrosis present in our cohort. Since these patients did not have late enhancement CMR, the level of scarring and myocardial fibrosis is unknown. Additionally, the sensitivity of ECM, which measures epicardial activation times, to identify small, potentially intramural, late activating regions may be much less than invasive electroanatomical mapping studies. Finally, it is not possible to analyse septal depolarisation as this is not observed during epicardial mapping.No significant difference was observed in TVaT and VaTThe study only considered a single acute measure, either ECM or echocardiogram to optimise device timings. Novel blood biomarkers are potential diagnostic and prognostic markers in an acute heart failure setting –30. ExteEchocardiographic programming optimisation does not result in the fastest possible biventricular activation. Instead, activation was consistently more rapid when optimised via ECM than with echocardiographic optimisation. ECM-guided programming optimisation may achieve superior fusion of activation wave fronts leading to improvements in CRT response.


This is a case-control study conducted on 30 children, 15 with VSD who performed VSD transcatheter device closure (group A) and 15 controls of matching age and gender (group B), in the period between September 2015 and February 2018. We aimed to assess the global left ventricular (LV) systolic function by 2D speckle tracking before and after ventricular septal defect (VSD) transcatheter closure, in comparison to normal controls. All patients were subjected to full history taking; general and cardiac examination; ECG; CXR; full transthoracic echocardiographic examination, including VSD number, size, and site; LV dimensions and volumes; estimated pulmonary artery pressure; right ventricular size and function; left ventricular circumferential; and radial strain imaging by 2D speckle tracking. Patients who had ventricular septal defect closed were reassessed by transthoracic echocardiography after 3 months.The study included 15 children with VSD: 3 males and 12 females; their age ranged from 2 to 13 years; all had subaortic VSD except for 1 who had apical muscular VSD: VSD size ranged from 3 to 8 mm; PFM coil was used to close defect in all patients except for 2 patients who had an Amplatzer duct occlude I (ADOI) device, and 1 patient needed an additional vascular plug after significant hemolysis. Pre-procedurally, group A had a significantly higher LVEDD, LVESD, and LVEDV than group B. Mean circumferential strain was significantly higher (more negative) in group A than that in group B either pre- or post-procedure. Post-procedurally, there was a significant decrease in circumferential strain (less negative) and a significant increase in radial strain (more positive).Following transcatheter VSD closure, there is a significant decrease in LV circumferential strain and a significant increase in LV radial strain, which conclude a decrease in LV volume overload with the improvement of its contractility. Ventricular septal defect (VSD) is the most common congenital heart disease accounting for 40% of all congenital heart diseases. An isolated VSD accounts for more than 20% of all congenital heart diseases . It is cManagement in the infant and child depends on symptoms; children with small asymptomatic defects need no medical management and are unlikely to need any intervention. First-line treatment for moderate or large defects affecting feeding and growth is with medical treatment for heart failure and high-energy feeds to improve calorie intake. Any patient needing significant medical management should be referred for surgical assessment .For a long time, the only way to close VSDs was open-heart surgery. This is a major procedure that necessitates a thoracotomy, heart-lung bypass, blood transfusion in some cases, permanent scar and potential risks of complete heart block, residual shunt, early and late arrhythmias, and post-pericardiotomy syndrome , yet surThe most widely used echocardiographic parameter to quantify left ventricle (LV) systolic function has been LV ejection fraction (LVEF). While LVEF is a strong predictor of mortality and is used to select patients for device implantation , surgicaNewer two-dimensional speckle tracking imaging (2D STI) allows for quantitative investigation of global and regional myocardial wall motion and deformation , 16, andAfter surgical VSD closure, 2D STI detected significant regional depression at the mid-ventricular level according to the peak circumferential strain variables, with no significant regional depression observed according to the peak systolic radial strain variables . TherefoThis study was conducted on 30 children, 15 patients with VSD who were referred to perform VSD transcatheter device closure and 15 control children , in the period between September 2015 and February 2018.Patients with contraindication to transcatheter closure, i.e., large size VSD, Eisenmenger’s syndrome, other associated congenital heart diseases, rheumatic heart diseases, associated cardiomyopathy, irregular rhythm, or baseline LV dysfunction before VSD closure, were excluded from the study.After the approval of the Ain Shams University ethical committee, written informed consent was obtained from all the patients’ parents. All patients were subjected to full history taking including age, gender, history of parents’ consanguineous marriage, drug intake during pregnancy or exposure to irradiation, recurrent chest infection, delayed growth milestones, history of dyspnea, previous catheterization or surgery, time of VSD transcatheter closure, and cardiac catheterization details .Patients were examined for developmental milestones, signs of other congenital anomalies, or syndromic features, with an assessment of body weight (kg), height (cm), and surface area . Cardiac examination for the assessment of precordial bulge, scars of previous surgery, dextrocardia, left parasternal thrill, hyperdynamic apex, auscultation for heart sounds, additional heart sounds , systolic murmurs, and signs of cardiac pump failure (pulmonary or systemic venous congestion) was done.Standard 12-lead surface electrocardiography (ECG) before and 3 months after the procedure was done to assess the following: rate, axis, arrhythmias , chest X-ray (CXR), and routine laboratory investigations including complete blood count, liver and renal function tests, and bleeding profile.All echocardiographic measurements were obtained at baseline and more than 3 months after the procedure using a Philips IE33 echocardiography machine, with S5-1 transducer. Pediatric patients who could not lie still were sedated using chloral hydrate in a dose of 50 mg/kg. The complete diagnostic transthoracic examination was done by 2D echo, Doppler, and color flow mapping, applying the sequential analysis technique from all available windows, identifying the size and site of VSD, number of VSDs if multiple, and direction and pattern of flow across.LV assessment by m-mode in PSAX view at the level of MV chordae was done to assess LVEDD (left ventricle end-diastolic dimension), LVESD (left ventricle end-systolic dimension), wall thickness, and EF (ejection fraction) and by the modified Simpson method from apical 4-chamber and 2-chamber views to assess LVEDV (left ventricle end-diastolic volume), LVESV (left ventricle end-systolic volume), and EF Fig. .Fig. 1LVCircumferential and radial strain imaging by 2D speckle tracking echocardiography was done as follows: high-quality ECG-gated images from the parasternal short-axis  views were obtained. All images were stored in cine-loop format from three consecutive beats, views were optimized through changing the transducer scan width to achieve a frame rate of at least 40 Hz, and data were transferred to a workstation for further offline analysis to assess the peak circumferential and radial 2D strain.Speckle tracking analysis for the LV was performed and consisted of marking the endocardium, defining the width of the region of interest, reflecting the distance from the endocardium to the pericardium, and running the automatic analytic algorithm. Within the defined region of interest, the software performed motion analysis of natural acoustic markers (speckles). The circumferential and radial peak systolic strain was calculated for each segment Fig. .Fig. 2MeThe operator who performed the follow-up TTE (transthoracic echocardiography) after 3 months was blinded to the pre-procedural TTE results and any clinical or catheterization data.Normal mean values of circumferential strain (CS) varied from − 10.5 to − 27.0 . Radial strain (RS) normal mean values varied from 24.9 to 62.1 . Table The transcatheter VSD device closure was done as follows: patients received general anesthesia on 100% oxygen under TEE  guidance; full hemodynamic study was done including the assessment of pulmonary artery pressure, systemic pressure, LV and RV (right ventricle) saturation, assessed VSD size, site, number from LV angiography in LAO 60, and cranial 30 projection with proper selection of size of the device accordingly; the device size (waist diameter) was selected to be 1–2 mm larger than the largest measured diameter of the defect. After device positioning and before its release, proper positioning, residual flow, and any affection on aortic, mitral, or tricuspid valves flow were properly assessed by TEE and LV angiography  version 24. Variables were expressed as mean ± standard deviation (SD). Comparisons between quantitative variables of groups were done using the non-parametric Mann-Whitney test. For comparison of serial measurements within each patient, the non-parametric Wilcoxon signed-rank test was used. Correlations between quantitative variables were done using the Spearman correlation coefficient. 2 (16.23 ± 3.65), and body surface area (BSA) ranged from 0.52 to 1.57 m2 (0.79 ± 0.24)  and 12 females (80%); their age ranged from 2 to 13 years (6.57 ± 3.62 years). Their weight ranged from 11 to 48 kg (22.89 ± 11.56), height ranged from 65 to 140 cm (114.8 ± 19.36), body mass index (BMI) ranged from 9.98 to 22.96 kg/m0% and 12All patients were asymptomatic except for 8 patients who had a recurrent chest infection. On the examination, only seven patients had shifted hyperdynamic apex denoting dilated LV. All patients had a harsh pan-systolic murmur of VSD on auscultation, and five patients had a soft pan-systolic murmur of MR with maximum intensity over the apex radiating to the axilla. All patients’ laboratory investigations were within normal.All patients had successful transcatheter closure of their VSDs as defined by Carminati et al. in 2007  [All patients had normal sinus rhythm as confirmed by their ECGs pre-procedurally. Two patients had complicating sinus bradycardia after VSD closure, one of them had resting HR of 53 bpm with first-degree heart block (first-degree HB resolved 24 h after the procedure) and the other had a resting heart rate of 55 bpm. Both patients were asymptomatic and were followed up.All VSDs were subaortic perimembranous except for 1 patient who had apical muscular VSD. Using transthoracic echocardiography, the VSD’s size from the left ventricular side ranged from 5 to 14 mm with a mean size of 10.8 mm and from the right side ranged from 3 to 8 mm with a mean size of 5.3 mm. All patients had one VSD except for 2 patients, who had 2 (subaortic perimembranous) VSDs. PFM coil was used for all patients except for 2 patients where the ADO I (Amplatzer duct occluder I) device was used . One patient needed an additional vascular plug (Table Ten patients (66.7%) passed smoothly without complications while five patients (33.3%) had complications in the form of the following: (1) mild AR post-procedure, (2) trivial TR pre-procedure which became mild TR post-procedure, (3) asymptomatic sinus bradycardia post-procedure, (4) asymptomatic sinus bradycardia and first-degree heart block that resolved spontaneously, and (5) significant hemolysis and residual defect managed by an additional vascular plug.There was minimal residual flow (1–2 mm by color Doppler) seen immediately after device implantation in 10 patients (66.6%) by TEE. After 3 months of follow-up, it decreased to 5 patients only (33.3%).2 vs. 56 ± 5.39 cm2) before and after the procedure (Table Echocardiographic parameters changed in group A (pre- and post-procedure) including the LVESD (24.6 ± 3.02 vs. 23 ± 2.75), LVEDD (38.87 ± 4.41 vs. 37.4 ± 4.69), LVESV (22.8 ± 5.78 vs. 20.73 ± 5.33), and LVEDV (62.27 ± 21.22 vs. 54.8 ± 18.8); all had an insignificant decline after device closure, with an insignificant increase in LVEF  of group A (pre- and post-procedure) did not have a significant difference from group B, p = 0.826 and p = 0.209 respectively  of group A (pre- and post-procedure) was significantly higher than that of group B with p = 0.015. The mean pre-procedural RS was 26.08 ± 3.04 and post-procedural RS was 27.72 ± 2.68%, p = 0.034 (Table There was a significant decrease in CS (less negative) and a significant increase in radial strain (more positive) pre- and post-procedure, where the mean pre-procedural CS was − 28.37 ± 2.59 and post-procedural CS was − 26.59 ± 3.13%, Although surgical option is the gold standard in the management of ventricular septal defect, percutaneous closure of VSD can achieve good results in closing perimembranous and muscular VSDs with advantages of reduced psychological impact, less pain, shorter hospital stays, no need for admission to an intensive care unit, faster time to normal activities, and less mortality , 22.Our study included 30 individuals, with a mean age of 6.5 years. This is the same mean age of Pawelec-Wojtalik et al.’s  and XunmZ score from + 1.7 to + 0.7 (p < 0.001) after 2 years follow-up. This can be explained by the short follow-up duration (only 3 months) in our population which could not detect the reduction in LVEDD.In the current study, there was an insignificant decline in both LVEDD and LVESD; this differs from Pawelec-Wojtalik et al. , who repIn the current study, there was no change in LVEF after transcatheter closure, and this result was concordant with Pawelec-Wojtalik et al. , who rep. That is why we used this technique in this novel study to assess patients before and after transcatheter VSD closure.Speckle tracking echocardiography is a recently developed noninvasive ultrasound imaging technique for the quantitative evaluation of LV regional and global systolic function to detect subtle changes in the myocardial function , 26. ThaWe noticed that there was a significant increase in RS (26.08 vs. 27.72), which may conclude improvement of LV function after VSD transcatheter closure and a significant decrease in CS (− 28.37 vs. − 26.59) which may return to the abolishment of volume overload after VSD transcatheter closure.Elsheikh et al.  studied In the current study, the mean CS of patients before device closure was significantly higher than that of the control group. This is justified by volume overload caused by the VSD in all of our patients. The mean CS values decreased after VSD closure; however, they did not reach the control values. This can be due to short post-closure follow-up period (3 months only). We expect that longer follow-up is needed for these values to reach the control values.In our study, there was minimal residual flow seen immediately after device implantation in 66.6% of patients by TEE. After 3 months of follow-up, it decreased to 33.3%. This may be explained by subsequent endothelialization. The residual flow was related to the presence of aneurysmal tissue. Haas et al.  reportedSecondary valve dysfunction was present in 13% of patients in the current study. Mild aortic regurgitation is possibly related to the traction of the coil on the aortic valve after crossing of the defect and during delivery of the left ventricular side of the coil. Tricuspid valve affection was related to the close proximity of the defect to the atrioventricular valves. We concluded that the technical aspects during device implantation, disruption of chordae tendineae, and close proximity of the defect to the affected valves are possible contributing factors to valvular regurgitation.Yang et al.  reportedIn our patients, only one patient suffered from hemolytic anemia that required blood transfusion and re-intervention to close the residual shunt. She needed another vascular plug of 10 mm to completely occlude the residual VSD. Holzer et al.  and RodrHaas et al.  reportedSpence et al.  and OdemWe achieved successful closure in 100% of the cases. This may be due to the restrictive inclusion criteria for VSD transcatheter closure. This agrees with Rodriguez et al. , who conIn the current study, there was a significant increase in RS and a significant decrease in CS after VSD transcatheter closure, which conclude the decrease in LV volume overload with the improvement of its contractility. To the best of our knowledge, this topic was never published before. We are aiming to continue our work by increasing the patients’ number and follow-up duration to confirm the results.


Mitral regurgitation (MR) is a common disease affecting more than 4 million people in the United States and the European Union. A significant number of percutaneous valves have been developed recently, specifically designed for the mitral anatomy, and with a promising evidence of good procedural and echocardiographic outcomes. However, even if transcatheter mitral valve replacement (TMVR) will have a role in the future of percutaneous treatment of both functional and degenerative mitral regurgitation, percutaneous mitral valve repair will always play a vital role in the treatment of MR because of the favorable safety profile and the fact that it respects the native anatomy. In this review, we will discuss the new emerging technologies under development to treat mitral regurgitation focusing on different devices that aim to target different components of the mitral anatomy. Mitral regurgitation (MR) affects more than 4 million people in the United States and the European Union and its prevalence increases with age, reaching up to 1 in 10 adults aged 75 years or older . DegenerFor these reasons, emerging low risk percutaneous strategies are needed to treat MR in both degenerative and functional anatomies, and to minimize the potential complications associated with open-heart surgery. Percutaneous MVr technologies are required to replicate surgical mitral valve reconstruction, without disrupting the normal valve and ventricular physiology. In this review, we will discuss the potential future role of percutaneous MVr, offering an overview on the emerging technologies that are currently under investigation.The degree of MR reduction with percutaneous repair technologies is not fully predictable, and a complete resolution is rarely guaranteed.Mitral valve anatomy is complex and different mechanisms can contribute to regurgitation. As a consequence, a single repair device addressing a single target will unlikely achieve optimal results. For example, a certain degree of mitral annular dilatation is always present in patients suffering from severe MR. Surgical MVr usually combines various types of leaflet-plasty with annular reduction in order to minimize the risk of progressive annular enlargement and MR recurrence . On the The mitral annulus is a highly dynamic, asymmetrical structure, with a saddle-shape conformation that poses difficulties in the positioning and sizing of these devices. Therefore, the development of percutaneous annuloplasty systems has to overcome major design obstacles due to the aforementioned complex mitral annular structure. A circular prosthetic ring runs the risk of not matching the asymmetrical anatomy of the native mitral valve annulus, thus increasing the tension between the device and the mitral structure. This limitation along with the method of fixation (screws) could translate into an increased risk of late device detachment, which has already been observed in the early cases of percutaneous mitral annuloplasty .A certain proportion of mitral anatomies are not the ideal candidates for repair and sometimes TMVR can be an alternative treatment option. Nevertheless, calcific and rheumatic MR still represent important unmet needs in transcatheter mitral intervention that may be associated with suboptimal results, both for repair  and replacement .A variety of repair techniques  has been introduced since the first MitraClip procedure in 2003. However, in most of these cases, emerging technologies have been dismissed because of suboptimal pre-clinical results, complicated implants, and difficult reproducibility of their results. The development of transcatheter MVr systems is facing the following challenges:Taking into consideration the aforementioned challenges, a significant number of percutaneous valves have been recently developed, specifically designed for the mitral anatomy, and with promising evidence of good procedural and echocardiographic outcomes. However, even if TMVR will have a definite role in the future of percutaneous treatment of both FMR and DMR, percutaneous MVr will always play a vital role in the treatment of MR due to the following:Technical aspects: Transcatheter valves and percutaneous annuloplasty devices have to adapt to the mitral annulus that, conversely to the fibrous ring of the aortic valve, does not provide a rigid anchor for sealing. Moreover, the mitral annulus is posteriorly embedded in the junction of the left atrium and left ventricle, while the anterior portion consists of the aorto-mitral curtain, a dynamic structure with limited rigidity. This poses multiple challenges for securing a device and bares the risk of compression and interference with the aortic valve apparatus. Data from the preliminary experience of these devices demonstrates that the risk of complications like valve erosion, migration, malposition at 1-year follow-up is around 4%  places it at a higher risk for obstruction, especially with high-profile valves. In one study on the early experience with TMVR, the rate of acute LVOT obstruction was 8.2% with transcatheter mitral valve-in-ring (ViR) procedures, and 9.3% following TMVR in the presence of severe mitral annular calcification (MAC) , 12. Aculacement . LVOT obLastly, the anatomical position of the mitral valve apparatus can be easily reached through a transapical approach. However, in sick patients with low ejection fraction, the presence of apical scar, and thinning of the apical wall are deleterious, thus an alternative access would be preferable to minimize the risk of complications. A fully percutaneous transfemoral trans-septal venous approach would be desirable but, in comparison to MVr, it would imply larger iatrogenic interatrial defects and it would require a highly flexible delivery system to coaxially reach the mitral valve plane .Durability: Although no long-term durability data exist for TMVR, we know from surgery that structural valve degeneration occurs more frequently in mitral bioprosthetic valves than in the aortic valves, and in younger individuals : Paravalvular leak (PVL) is a common complication of mitral valve replacement . The system is composed of eight stainless-steel anchors that are connected by sliding collars and nitinol frames, located in the upper position of the device. Each anchor can be independently and reversibly fixed to the mitral tissue in order to customize the size and the site of anchoring. The Millipede IRIS has been implanted both surgically, using a trans-atrial approach, and percutaneously, with a 24 French steerable catheter delivered trans-septally. The first clinical experience with IRIS included seven patients: four were treated using a conventional surgical approach, while three patients were treated percutaneously. The percutaneous implant of the device was monitored under fluoroscopy and using both transesophageal and intracardial ultrasound (ICE) monitoring. The adjunctive use of ICE allowed a direct visualization of the mitral annulus and a detailed placement of the IRIS anchors. All the iatrogenic atrial septal defects were closed with a 10 mm Amplatzer septal occluders . The authors reported no major adverse events and a procedural success obtained in all the cases. The implant resulted in a significant reduction in the septo-lateral diameter (from 38.0 ± 4.1 to 25.9 ± 4.9 mm), and in a significant reverse remodeling of the left ventricle, with a decrease in diastolic left ventricular volumes from 182.4 ± 54.3 to 115.3 ± 98.8 mL at 30 days. Every patient demonstrated reduction of MR, with all patients showing a decline from a baseline of 3 or 4+ MR to 0 or 1+ MR at 30 days . One of The Annular Reshaping of the Mitral Valve for MR Using the Millipede IRIS System (NCT02607527) is an early feasibility clinical trial with the aim of enrolling 50 patients with symptomatic severe MR treated percutaneously with the IRIS device.2, and regurgitant volumes from 45.4 ± 15.0 to 19.5 ± 10.2 ml. The mitral annular anteroposterior diameter decreased from 45.0 ± 3.3 to 38.7 ± 3.0 mm. One patient had pericardial effusion, and one asymptomatic device dislodgment were reported at 30-days, with no other major adverse events  is an incomplete and indirect annuloplasty system. The system is composed of two magnets (MagneCath) that are placed in the great cardiac vein and in the left atrium at the level of A2/P2 scallops. Once the two magnets are close to each-other, a specific guidewire is passed through the two MagneCath from the great cardiac vein to the left atrium, aligning the two catheters. After using an exchange catheter, the loop guidewire is placed across left atrium. This guidewire directs the placement of the great cardiac vein anchor (T-bar) and septal anchor. Once in place, an appropriate tension is applied to reduce the antero-posterior dimension of the mitral annulus. The results of the Mitral Valve Repair Clinical Trial (MAVERIC) have been published, where the authors reported the 30-days outcome of 11 patients that were treated with the MVRx ARTO system. Effective regurgitant orifice area decreased from 30.3 ± 11.1 to 13.5 ± 7.1 mme events . To evalValcare Amend system  is a complete, semi-rigid D-shaped percutaneous annuloplasty system. The ring is available in three sizes to fit a wide range of mitral annular dimensions (29–50 mm). Once in place, the ring is delivered starting from the posterior part of the annulus. The annuloplasty ring is designed to be delivered through a transseptal or a trans-apical approach. This annuloplasty system has been tested in different scenarios and in combination with other therapies. A total of 14 patients have been treated in the first clinical experience: eight patients with FMR have received Valcare Amend as a single therapy. Whereas, two patients with DMR have received Valcare Amend as a single therapy. In another four patients, the system has been utilized in combination with MitraClip (three patients) and with NeoChord (one patient). The implant resulted in a 74% reduction of the jet area and in a 20% reduction in the antero-posterior diameter . In a siThe Accucinch GDS device  is a direct ventriculoplasty system targeting the sub-annular left ventricular myocardium. The system includes a delivery catheter, a modular guide tunnel (MGT), an anchor delivery catheter and 12–16 nitinol anchors, connected by an ultra-high molecular weight polyethylene cinch cable to exercise tension over them. Proximal and distal anchors are interspaced with nitinol force distribution members. The system is implanted retrogradely using an 18 French guiding catheter delivered through the aortic valve. The Accucinch GDS implant can be customized according to the sub-annular space anatomy and to the thickness of the left ventricular wall. Anchors are delivered from commissure to commissure through an arch beneath the posterior leaflet of the MV in the ventricular free wall. Once the system has reached the sub-annular space, the MGT is oriented in direction of the myocardium and gradually withdrawn to facilitate anchor delivery through an inner tunnel with a single window. Once all the anchors have been released, tension is applied to the cinch cable using the cinch and lock catheter. A cut catheter is then utilized to cut the cinch cable before removing the MGT and the guide catheter . Thanks The Transmural System Transcatheter Mitral Cerclage Annuloplasty  is an indirect annuloplasty system composed of a stainless steel tension element with a coronary artery protection system. The two extremities of the tension element are connected using a bridge device that extends to the left subclavian vein. An adjustable extravascular lock is fixed subcutaneously in the subclavicular fossa and has the function to connect the tension element and the bridge, thus allowing a modulation of the tension under echocardiographic monitoring .in situ, the bifid coronary sinus tricuspid valve bridge is placed to prevent any damage of the septal tricuspid leaflet and of the conduction system. The first in human experience with the mitral loop cerclage annuloplasty was successful in 4 of 5 attempts. The mitral regurgitant volume and the septo-lateral mitral annular diameter were significantly reduced at 6 months . The implantation of the mitral Cerclage also lead to a reduction of the left ventricular end diastolic volume (140 ± 62.5–102.6 ± 35.7 ml)  is a newly developed system that targets the sub-annular apparatus, and acts as a chordal system that can be implanted using a transfemoral trans-septal approach. Once the delivery catheter reaches the left ventricle, a ventricular anchor is deployed from the catheter and fixed to the free wall, leaving a ventricular suture attached to the ventricular anchor. A leaflet pledget is deployed to secure the mitral valve leaflet to the ventricular anchor. The leaflet suture is secured to the ventricular anchor to limit the excursion the leaflet. This technology is currently under pre-clinical investigation with mid-term ovine models showing the feasibility of the procedure.P < 0.001), with <1+ MR in 33/34 patients . At 2 years, the mean mitral gradient was 2.15 ± 0.82 mmHg, and the mitral annular septo-lateral dimension decreased from 40.4 ± 2.91 to 28.9 ± 1.55 mm  is a newly developed technology that consists in a curvilinear nitinol band covered by a silicone overmold with velour pads at either extremity. The Mitral Bridge is positioned transversely across the mitral valve, linking the anterior and the posterior leaflets at the level of A2-P2 segments, thus reducing the antero-posterior annular dimensions. A delivery handle, preattached to the implant, assists in positioning the bridge on the annulus with the curvature facing the ventricular cavity. Five septal-laterally oriented sizes of the mitral bridge  are available. The initial experience included 34 patients enrolled in the observational study of the Heart Repair Technologies Mitral Bridge in Treating Mitral Valve Regurgitation (NCT03511716), who received a surgical implant of the Mitral Bridge. At 2 years, no strokes or device-related adverse events were noted, and the MR was reduced from 3.32 ± 0.47 to 0.50 ± 0.83  is a fully percutaneous transcatheter mitral chordae implantation system, which can be delivered through the transtrially or transfemorally via the trans-septal approach. ChordArt uses a dedicated delivery catheter that grasps the mitral leaflet in the target area that needs to be treated. Once grasped, the delivery system is passed through the punctured leaflet until it reaches the papillary muscle. Once at the level of the papillary muscle, an anchor located at the distal tip of the catheter is fixed into the muscle. After this maneuver, the delivery system is retrieved leaving a suture that connects the grasped leaflet and the subvalvular apparatus. Pre-clinical studies have evaluated the safety and the efficacy of the system, surgically implanted in the beating heart of five sheep with acute chordal rupture; all procedures were successful and all of the five animal models were alive at 6 months follow-up, with no evidence of disruption or malfunction of the device. The ChordArt system has been subsequently implanted also in five pigs with acute mitral valve chordal rupture. The device has been implanted under fluoroscopy and echocardiographic guidance using left thoracotomy, with direct access through the left atrium on a beating heart. After the positive first in human experience for compassionate use, the device performance and the technical efficacy of ChordArt is currently under investigation in the ChordArt System for Mitral Regurgitation trial  with the planned enrollment of 40 patients suffering from a flail or prolapsed mitral valve leaflet  is a transcatheter mitral valve chordal repair technology designed for the treatment of DMR due to prolapsed or flail leaflets. It is still in the research and developmental phase. It requires a transfemoral venous access and a transseptal puncture to reach the left atrium. The device is advanced through a 24Fr steerable delivery catheter to grip the prolapsing leaflet, then the new chordae is attached from the leaflet to the ventricular wall, where an anchor fixes it. Anchors are removable and repositionable. Studies to assess safety and feasibility are needed.(Heartworks LLC) is a new sutureless leaflet plication device designed for treating patients with mitral leaflet prolapse through a transcatheter approach. The U-shape arms are able to rotate around a common axis. Following leaflet grasping, leaflet plication is performed by rotating the two arms in two opposite ways. Pre-clinical study on the application of the MitraClamp in six fresh pig hearts demonstrated a dramatic reduction of the regurgitant volume during hydrodynamic tests. Device anchorage to leaflets was also found to be stable after device locking  is a transcatheter MVr technology performed through a transapical access . Under general anesthesia and transesophageal echo guidance, it allows the placement of expanded polytetrafluoroethylene (e-PTFE) sutures as replacement neochordae on a beating heart, without the need for cardiopulmonary bypass .A relatively short learning curve is needed to achieve expertise in performing the NeoChord procedure safely . This coA currently ongoing multicenter, randomized trial (NCT02803957) comparing the NeoChord procedure with conventional surgical MVr in the United States will help provide further insights on the procedure.The mitral Butterfly system  aims to reproduce the butterfly repair technique for the treatment of the posterior MV leaflet prolapse. The butterfly repair consists of the combination of a triangular resection from the prolapsing edge, with a reverse triangular resection to the annulus to remove redundancy . The ButThe Polares  solution is a new concept in the vast armamentarium of mitral valve transcatheter technologies, it is a halfway between repair and replacement. It consists of the implantation of a posterior ePTFE neoleaflet to restore coaptation with the valve's native anterior leaflet. The development of this technology still needs to undergo clinical testing. To this date, implantation has been only performed in animal models.The MitraMaze system  is a coaptation enhancer device composed of a flexible spacer, a nitinol crown and a customized delivery catheter system, which is specifically designed for the transfemoral approach. Upon release on site in the beating heart, the self-expanding implant design allows for an atraumatic anchoring in the left atrium, without the need to include adjacent myocardial tissue structures. A nitinol crown is left in the atrium and the spacer can be filled to reduce the coaptation gap between the mitral leaflets. In ovine models, the MitraMaze has demonstrated a significant reduction of the regurgitant volume .The Sutra (Dura Biotech) hemi-valve has been studied to specifically treat MR secondary to an isolated defect of the posterior mitral valve leaflet. The hemi-valve is composed of a tri-leaflet valve mounted on a crescent shaped stent frame. The hemi-valve is designed to enhance the systolic coaptation with the native leaflets, thus reducing the regurgitation. The hemi-valve is fixed to the posterior annulus through anchors that can be adjusted, thus allowing the possibility to cinch the native valve annulus. The first generation device has been surgically implanted in animals due to the lack of an anchoring system. However, the latest version of the device has been implanted in animals using the anchoring system. The device has demonstrated good safety and efficacy in reducing the regurgitant volume under hydrostatic testing .Percutaneous MVr is a rapidly growing field, with several devices at different stages of development. Due to their capacity to preserve the complex inner anatomy of the mitral valve, these repair systems will have an important role in the treatment of MR. Large clinical cohort studies will help identify the right patient population that would benefit the most from transcatheter MVr. This breakthrough of new repair devices will enlarge the percutaneous armamentarium of MVr, offering a wide possibility of treatments customizable to specific anatomical features.AM, ALar, FGi, and FGa produced a first draft of the manuscript. FK, ALad, and LT did a review of the literature. AC and ALat reviewed the article and gave their intellectual contribution to the manuscript.AM received an institutional grant (unrestricted grant) from Boston Scientific; he received a research grant from Innovative Cardiac Solution. FGi serves as proctor for Neovasc, ALat has served on advisory boards for Medtronic and Abbott; and has been a consultant to Edwards Lifesciences. The remaining 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.