Objectives: Decellularized extracellular matrix (dECM) is increasingly used in a wide range of regenerative medicine applications and may also offer the potential to support injured myocardium. Here, we evaluated the myocardial gene expression pattern after myocardial infarction (MI) in a standardized rodent LAD-ligation model with and without ventricular stabilization with a customized, cardiac dECM-based scaffold (cdECM).Methods: MI was induced in male Wistar rats by standard LAD-ligation and confirmed 14 days post-intervention by echocardiographic parameters (FAS<40%). Cardiac ECM from donor rats was used to generate individual cdECM-scaffolds , which were epicardially implanted after confirmed MI for ventricular stabilization. After 4 and 8 weeks heart function was assessed by echocardiography, rats were sacrificed and explanted hearts were analyzed. In addition to histological analysis, standardized anterior left ventricular wall myocardial tissue samples were assessed by quantitative real-time PCR evaluating the specific gene expression pattern for immunomodulatory , pro-angiogenic , pro-survival , remodeling-associated  and infarction-specific  markers.Results: Ventricular stabilization led to integration of the TEMS-scaffold into the myocardial scar with varying degrees of cellular infiltration, as well as significantly improved echocardiographic parameters demonstrating attenuation of maladaptive cardiac remodeling. Further, TEMS implantation after MI altered the myocardial gene expression pattern. Differences in gene expression were most striking after 4 weeks with significantly reduced expression of NPPA , NPPB , TGFBR2  and PDGFB  as well as increased expression of IL-10 , PGF  and IGF1 . However, after 8 weeks differences in the gene expression patterns of remodeling-associated, and pro-angiogenic markers could still be observed between groups.Conclusion: Ventricular stabilization via TEMS implantation after MI did not only led to biological integration of the cdECM-scaffolds into the host tissue and improved functional cardiac parameters, but also altered 4 and 8 week gene expression of infarcted myocardium, possibly contributing to reducing chronic deteriorating effects while increasing the potential for myocardial regeneration. Decellularized extracellular matrix (dECM) based scaffolds are increasingly used in a wide range of regenerative medicine applications, as they maintain the complex microarchitecture and ultracomposition of native tissues and hence provide ideal cues for tissue regeneration . In the in vivo model.Here, we introduce a new therapy concept using a customized, decellularized cardiac ECM-based scaffold (cdECM-scaffold) in form of a tissue engineered myocardial sleeve (TEMS) for ventricular stabilization after myocardial infarction, hypothesizing that this might stimulate myocardial regeneration, hinder adverse cardiac remodeling and improve cardiac hemodynamics. This proof-of-concept study focuses on the effect on myocardial gene-expression after ventricular stabilization via TEMS in a standardized rodent LAD-ligation All animal experiments and surgical procedures were performed in compliance with the Guide for the Care and Use of Laboratory Animals as published by the US National Institutes of Health  and approved by the local animal care committees (Registration No. 84-01.04.2012. A335).in toto heart decellularization was performed via standardized automated software-controlled coronary perfusion with decellularization agents as previously described  were explanted and perfusion based escribed . BrieflyCustomized, decellularized cardiac ECM-based scaffolds (cdECM-scaffolds) where obtained through standardized microsurgical dissection of the decellularized whole-hearts. Therefore, the atria including the atrioventricular heart valves, the septum and the apex of the decellularized whole-heart were removed, leaving a myocardial sleeve consisting of the free walls of the right and left ventricle  . Dissectin situ for either 4 or 8°weeks, after which the experimental animal was euthanized, the heart explanted and analyzed .In order to evaluate the biological effects of ventricular stabilization with a cdECM-scaffold after myocardial infarction we used a standard rodent LAD (left anterior descending coronary artery)-ligation model with Wistar rats  as animal model. Fourteen days after LAD-ligation the cdECM-scaffold in form of a TEMS was then epicardially implanted and left nalyzed .LAD-ligation induced myocardial infarction was confirmed by standard echocardiographic parameters . Only anad libitum with standard rat chow, were used as a rodent animal model. For LAD-ligation, rats were anesthetized with 2.0–2.5% isoflurane, orotracheally intubated and machine ventilated with room air supplemented with oxygen using a small animal ventilator . The respiratory rate was adjusted to maintain the partial pressure of CO2 within physiological limits. Body temperature was maintained at 37°C–37.5°C with a heating pad. Baseline echocardiographic parameters were recorded, and afterwards a lateral left-sided thoracotomy was performed. After pericardiotomy, the heart was exposed, the left anterior descending coronary artery (LAD) was identified and a 10–0 monofilament non-absorbable polypropylene suture  was looped around the LAD and ligated. Coronary artery occlusion was immediately verified by blanching and cyanosis of the myocardial area at risk . After LAD-ligation the thoracotomy was closed in layers. For LAD-ligation sham operation  the suture was only looped around a major branch of the LAD and removed, without ligation.For induction of myocardial infarction, a standard LAD-ligation model was used . Wistar TEMS were implanted 14 days after LAD-ligation (or sham operation). Therefore, rats were anesthetized, orotracheally intubated and machine ventilated as described above. Echocardiographic parameters were recorded in order to evaluate efficacy of prior LAD-ligation. Afterwards thoracotomy was performed using the surgical access site from the prior operation in order to expose the heart. The TEMS was slipped over a copped 2 ml syringe , whose opening was used to apply gentle suction force on the apex, luxate the heart ventrally and pull the TEMS over the native heart. TEMS was aligned anatomically correct  and fixated with four stitches using 10-0 Prolene suture  so that it covered most of the surface of both ventricles  . After iFour and 8 weeks after TEMS implantation or sham operation experimental animals were narcotized and echocardiographic parameters were recorded. After euthanasia the heart was explanted via median sternotomy and processed depending on subsequent tissue analysis..Echocardiographic assessment was performed on anesthetized animals at baseline, 14, 42 and 70 days, according to the experimental protocol, using a Philips HDX11 ultrasonography system equipped with a 15- MHz probe . Following parameters were evaluated in a standardized analysis: left ventricular end-diastolic diameter (LVEDD), ejection fraction (EF) and fractional area shortening (FAS) of the left ventricle .For orientating histological analysis, explanted hearts were dissected into standardized slices, fixed in a 4% buffered formaldehyde solution  and processed via cryo-sectioning  using standard protocols. Frozen sections of 6 mm were then stained with hematoxylin and eosin (H&E) and Movat’s pentachrom staining according to standard protocols, and then visualized using a transmission light microscope .For evaluation of gene expression, freshly explanted hearts were dissected into standardized probes separating the TEMS from the native heart . Probes were then snap-frozen in liquid nitrogen and pulverized. RNA was isolated of processed tissue samples using the RNeasy Mini Kit  according to the manufacturer’s protocol. RNA quality was analyzed by automated electrophoresis . Isolated RNA was subjected to cDNA synthesis using the QuantiTect Reverse Transcription Kit  according to the manufacturer’s protocol using a real time cycler . Synthesized cDNA samples then underwent real-time-polymerase chain reaction (qRT-PCR) to assess the expression levels of specific immunomodulatory , pro-angiogenic , pro-survival , remodeling-associated  and infarction-specific  genes using top2b as well as beta2‐microglobulin as respective house-keeping genes. Primers were selected from the National Center for Biotechnology Information (NCBI) database . Recordep-values were lower than 0.05. Data analysis was conducted with GraphPad Prism v5.04 .All values are presented as mean −/+ standard deviation of the mean for all continuous variables. For direct group comparisons at one single time point, Student’s t-tests with or without Welch’s correction or Mann–Whitney U tests were performed. Statistical significance was assumed if Ventricular stabilization with a cdECM-based scaffold via TEMS-implantation either with or without LAD-ligature was performed in 56 animals. Peri- and postoperative mortality was 35.7% and mostly due to perioperative complications either related to the anaesthesia or the surgical procedure. Mortality after successful TEMS implantation was neglectable, with 36 animals (64.3%) reaching the end of the experiment after 4 or 8 weeks. Together with the respective sham control groups 86 animals reached the endpoint and were analysed.p < 0.0001) and a significant increase in LVEDD  after 14 days, as compared to the sham control group (p = 0.13) with however significant improved EF  as well as FAS , as compared to the respective shame control group (+LAD/-TEMS) after 4 weeks (p < 0.0001) with further increase in EF  as well as LV-FAS , as compared to the respective shame control group (+LAD/-TEMS)  . TEMS-imD/-TEMS) .in vivo the TEMS scaffold had adhered to the epicardium and seemed to be especially integrated to the native tissue in the infarct area. TEMS scaffolds could however be mechanically removed from the heart for further analysis.Representative images of explanted heart specimens 4 weeks after TEMS-implantation are shown in LAD-ligature led to classical histological findings after myocardial infarction with formation of granulation tissue, neovascularization and decreased cellularity (data not show). Ventricular stabilization via TEMS implantation led to biological integration of the TEMS scaffold to the native myocardium with native cells infiltrating the TEMS scaffold . As oppoin vivo cellular infiltration, the explanted TEMS tissue contained high degrees of RNA, ranging between 40% and 70% of the RNA concentration in the adjacent native myocardial tissue. In the TEMS tissue adjacent to the infarcted region of the heart, RNA concentration was 238.5 ± 102.8 ng/μl after 4 weeks and 161.04 ± 92.65 ng/μl after 8 weeks in vivo, as compared to 354.2 ± 92.0 ng/μl and 331.8 ± 128.5 ng/μl in the respective adjacent anterior wall of the LV.Evaluation of TEMS tissue prior to implantation revealed no detectable RNA in the cdECM scaffolds. However, due to the As expected, myocardial infarction via LAD-ligation did significantly changed the expression pattern of the analyzed genes in the infarcted myocardial area of the left anterior ventricular wall after 4 as well as 8 weeks, as compared to the respective sham control group (-LAD) . In the Gene expression of the myocardial tissue within the infarcted region was further altered after ventricular stabilization via TEMS-implantation, as compared to the respective sham control group (+LAD/-TEMS) . Differe,in situ the TEMS scaffold on infarcted myocardium showed significantly increased expression of pro-angiogenic PGF  and reduced PDGFB , increased expression of remodeling-associated TIMP1  and reduced expression of MMP9  as well as reduced infarction-related expression of NPPB , as compared to the TEMS scaffold placed on non-infarcted myocardium . After 8 weeks in situ the TEMS scaffold on infarcted myocardium showed significantly increased expression of immunomodulatory TGFBR2 , decreased expression of pro-angiogenic VEGFA , as well as reduced infarction-related expression of NPPA  and NPPB , as compared to the TEMS scaffold placed on non-infarcted myocardium .Interestingly, cells in the TEMS scaffold had a different gene expression pattern depending on whether the cdECM scaffold was placed on healthy or infarcted myocardium ,. After 4ocardium . After ocardium .in vivo.This proof-of concept study demonstrates that ventricular stabilization after myocardial infarction with a customized, decellularized cardiac ECM-based scaffold (TEMS) significantly alters myocardial gene expression in a rodent LAD-ligation model. Further, orientating analysis shows improved functional echocardiographic parameters as well as biological integration of the TEMS scaffold after 4 and 8 weeks of ventricular stabilization In the past, different surgical and experimental approaches have used the concept of cardiomyoplasty in terms of functional left ventricular restoration in order to treat end-stage heart failure. This concept was first introduced in 1985 by Carpentier and Chaques as dynamic cardiomyoplasty, by wrapping the M. latissimus dorsi circumferentially around the heart in order to support systolic contraction . AnotherAs shown in this study ventricular stabilization via TEMS implantation prevents progressive left ventricular dilatation after myocardial infarction. Rats with supported ventricles via TEMS implantation after LAD-ligation did not only present with significantly smaller LVEDDs after 8 weeks as compared to their controls, but also showed LVEDDs comparable to the values at the time-point of TEMS implantation 14 days after myocardial infarction. Together with the other functional echocardiographic parameters, this demonstrates the potential of the TEMS concept to prevent adverse cardiac remodeling. It is still unclear what triggers this effect. Decellularized cardiac ECM still has a certain stiffness which might offer passive mechanical support during diastole , leadingThe alteration of the gene expression pattern of the infarcted myocardium depending on whether the LV was supported by TEMS implantation or not, as well as the different gene expression pattern of the cells infiltrating the TEMS scaffold depending on whether it was placed on healthy or infarcted myocardium, seem to demonstrate a high degree of biological interdependency. TEMS implantation seemingly inhibited an up-regulation of infarction-related NPPA and NPPB, while promoting a down-regulation of pro-angiogenic PDGFB and immunomodulatory TGFBR2 and an up-regulation of pro-survival IGF1 and immunomodulatory IL-10 after 4 weeks of ventricular stabilization. Multiple pathophysiological factors converge after myocardial infarction leading to adverse remodeling and ischemic cardiomyopathy . AlteratSince in this proof-of-concept study only an orientating histological analysis of the explanted TEMS specimens was conducted, it remains unclear which cells infiltrate the TEMS scaffold and what role they play in the observed effects with regards to cardiac remodeling and improved cardiac function. Interestingly though, gene expression patterns of those cells significantly varied depending on whether the TEMS was placed on infarcted or healthy myocardium. During implantation the TEMS scaffold is only loosely placed on the epicardium, therefore the cdECM-scaffold seems to inherently attract resident cells, which possess the ability to integrate the scaffold into the myocardial tissue especially in the region of infarcted myocardium. Recent research efforts are increasingly demonstrating the importance of epicardial-myocardial signaling and epicardial stem cells in cardiac repair . Therefoex vivo offering the possibility to enhance the TEMS concept with appropriate pro-regenerative cell populations potentially further increasing cardiac repair (Further, cardiac-derived decellularized ECM scaffolds can be repopulated c repair . This woc repair . Althougc repair . Here, tc repair . In factc repair .In conclusion, ventricular stabilization of the heart via a cdECM-scaffold in form of a TEMS stimulates myocardial regeneration, attenuates cardiac remodeling and improves cardiac hemodynamics in a rodent model. Hence, the TEMS approach might be a promising therapy strategy for inducing cardiac regeneration in diseased hearts following a novel bioactive cardiomyoplasty concept. However, further studies are warranted in order to confirm those findings and translate the concept into a clinical setting.As this is a first proof-of-concept study several limitations remain. Cardiac functional parameters are based solely on echocardiographic parameters and need to be validated with more sensitive analysis such as MRI or invasive catherization. Although gene expression analysis was mostly consistent between both housekeeping genes, there is still a large biological variability within the reduced sample size. Further analysis in order to elucidate on the mechanism behind the observed biological effects and to characterize infiltrating cells are warranted. As this study was conducted in a rodent animal model, results should be considered with caution when applied to humans.


Alteration of muscle activation sequence is a key mechanism in heart failure with reduced ejection fraction. Successful cardiac resynchronization therapy (CRT), which has become standard therapy in these patients, is limited by the lack of precise dyssynchrony quantification. We implemented a computational pipeline that allows assessment of ventricular dyssynchrony by vectorcardiogram reconstruction from the patient’s electrocardiogram. We defined a ventricular dyssynchrony index as the distance between the voltage and speed time integrals of an individual observation and the linear fit of these variables obtained from a healthy population. The pipeline was tested in a 1914-patient population. The dyssynchrony index showed minimum values in heathy controls and maximum values in patients with left bundle branch block (LBBB) or with a pacemaker (PM). We established a critical dyssynchrony index value that discriminates electrical dyssynchronous patterns (LBBB and PM) from ventricular synchrony. In 10 patients with PM or CRT devices, dyssynchrony indexes above the critical value were associated with high time to peak strain standard deviation, an echocardiographic measure of mechanical dyssynchrony. Our index proves to be a promising tool to evaluate ventricular activation dyssynchrony, potentially enhancing the selection of candidates for CRT, device configuration during implantation, and post-implant optimization. During its end-stages, this pathology is characterized by altered ventricular electrical activation and ventricular arrhythmia. One of the therapeutic approaches for end-stage heart failure consists in the implantation of cardiac resynchronization therapy (CRT) devices in a selected group of patients to improve the heart’s mechanical efficiency. Specifically, CRT is strongly recommended in patients with a left bundle branch block (LBBB) and reduced left ventricle (LV) ejection fraction with persistent heart failure symptoms despite optimal medical treatment. Also, CRT can be considered for other patients based on weaker recommendations3. When successful, this artificial stimulation from specific heart locations improves both mechanical cardiac efficiency and patients’ clinical condition. However, individual response to CRT is hard to predict: currently, up to 30% of all patients treated with CRT do not show significant clinical improvement4. Additionally, guideline recommendations are also believed to exclude other patients who could probably benefit from CRT, since the QRS morphology is not the only determinant of dyssynchrony5. An important source of this classification problem is the lack of a precise method for quantifying ventricular synchrony in order to identify patients with more dyssynchronous ventricular activations and, therefore, with higher chances to benefit from resynchronization. Thus, there is a clear clinical need for an accurate quantification of ventricular synchrony for predicting the therapeutic response to CRT. Additionally, this quantification could also be useful for guiding cardiac electrophysiologists in selecting the best configuration for each patient during or after CRT device placement.Chronic heart failure is one of the leading health and economical burdens worldwide, yielding high morbidity and mortality ratesAREA), which results from the numerical integration of the VCG vector magnitude over time 7. Similarly, other related magnitudes such as QRS-T area and QRSAREA in the Z dimension have also been proposed9.Recently, attention has been drawn towards vectorcardiogram (VCG) as a tool for cardiac electrical synchrony assessment in CRT candidates. Particular emphasis has been placed on attempting to predict CRT therapeutic response based on the quantification of VCG-derived QRS area (QRSAREA in particular open the possibility of further advances (see Discussion section). In this study, we propose a novel index to measure the ventricular electrical activation synchrony, implemented in a computational pipeline. After software validation using an online ECG database10, we applied our method to automatically analyse a local database of nearly 2000 ECGs. Finally, we investigated the link between our dyssynchrony index and mechanical heterogeneity in LV contraction by performing speckle tracking echocardiography during post implant follow-up in patients with pacemaker (PM) or CRT device.Although the aforementioned quantities represent an improvement compared to the current electrocardiographic-based CRT candidate selection criteria, the complexity of the determinants of cardiac synchrony in general and the complexity of the determinants of QRS11 (see Methods section), we reconstructed the VCGs of 49 control individuals, 9 patients with RBBB and 8 patients with LBBB. ECG signals were obtained from the online PTB Diagnostic ECG database available on the Physionet website12. The trajectory of the vectors in the three-dimensional space is clearly altered in the VCG of patients with RBBB or LBBB as compared with controls . On a scatter plot representing STI over VTI, the observations fitted neatly into a linear function  that represents the inverse of the tissue’s characteristic time and describes the relation between these two variables in the population of individuals without intraventricular conduction abnormalities. We hypothesized that the observations that lay in the proximity of the control population linear fit would belong to patients without intraventricular conduction alterations, while those far away would belong to patients with altered electrical conduction during the ventricle depolarization. More specifically, we entertained the hypothesis that the further from the control population line, the higher the dyssynchrony. To perform a quantitative assessment of our hypothesis we defined the dyssynchrony index as the normalized nondimensional perpendicular distance between the VTI-STI coordinates of an individual observation and the linear fit of the control population  (US database). The voltage and speed kinetics of the vectors of ventricular depolarization from this database overlapped the signals of the control individuals from the online PTB database Fig. . In acco13.Patients with LBBB or RBBB from the online PTB database lay mostly farther away from the control population’s fitted line on the STI over VTI plot. The median dyssynchrony index of patients with RBBB was higher than controls, although no significant  Fig. . PatientSince the dyssynchrony index could distinguish groups from an online database with clear differences in their level of dyssynchrony, we decided to test the ability of this index to discriminate among different degrees of dyssynchrony within a more complex and heterogeneous population of patients who displayed more diverse electrical conduction patterns, including—but not limited to—RBBB and LBBB. In order to do this, we retrospectively explored the ECGs of 1914 patients from the British Hospital of Buenos Aires, who were evaluated for suspected or confirmed arterial hypertension between February and November 2019 . We choose this population to expand the external validity of our results since it included a diverse group of patients with a wide range of comorbidities and clinical conditions and with varying types and degrees of conduction abnormalities. This population also included healthy individuals with suspected—but latter discarded—arterial hypertension.14. Disagreements between the two observers were identified and reviewed .As a first step, ECGs from the local BH database (n = 1914) were independently inspected by two experienced cardiologists and classified into one of eight groups, depending on the intraventricular conduction pattern , Incomplete Right Bundle Branch Block (IRBBB), Left Anterior Fascicular Block (LAFB), RBBB, Left Posterior Fascicular Block (LPFB), RBBB + LAFB, Incomplete Left Bundle Branch Block (ILBBB), LBBB and PM). Both cardiologists classified the ECGs according to pre-established criteria15. The overall behaviour of patients with LAFB, RBBB, RBBB + LAFB or ILBBB fell away from the control population line and presented varying dyssynchrony index values  into two groups: those with an electrical pattern that clearly conditioned dyssynchrony (patients with LBBB or PM) and those who’s electrical pattern could not be clearly categorized as dyssynchronous, at least not with a high level of certainty . Using a logistic regression model, we estimated the probability of being classified in each group based on the dyssynchrony index. Finally, we established the cut-off values that yielded the best discrimination performance among groups according to the highest Youden index18. Two echocardiograms and their corresponding ECGs were recorded for each patient before and after device configuration optimization, according to the physicians’ personal expertise  from 10 patients with PM or CRT devices, and compared our ECG-derived dyssynchrony index with the echocardiographic time to peak strain standard deviation (TPS-SD) as a marker of mechanical dyssynchrony 3. Although great efforts have been made to refine CRT indication criteria, around 30% of patients who receive this treatment obtain no benefit, leading to inefficient resource allocation and unnecessary patient risk4. On the other hand, guideline recommendations may also exclude patients who could be potentially benefit from CRT treatment, for example certain subgroups of non-LBBB patients21. Hence, the two main challenges CRT is currently facing are: how to accurately identify patients who will respond positively to treatment, and how to measure the improvement in synchrony produced by CRT in order to setup an optimal stimulation sequence. Both of these major issues are rooted in the lack of an accurate method for quantifying synchrony. Precisely, in this study we conceived, computationally implemented, validated, and tested a pipeline to extract an index of dyssynchrony from ECG-derived VCGs.Current heart failure and resynchronization guidelines clearly indicate the implantation of a CRT device in patients with LV ejection fraction below 35%, sinus rhythm, New York Heart Association functional class II, III, or ambulatory IV despite optimal medical treatment, and LBBB with a QRS width over 150 ms3. Though a dyssynchronous ventricular activation is characterized by an abnormally prolonged ventricular depolarization time, it is now clear that this is not the only factor at stake, and perhaps not even the most important one. Given the aforementioned high prevalence of CRT non-responders, new VCG-derived estimators of dyssynchrony have been proposed, such as the area under the curve of the ventricular depolarization vector magnitude versus time plot  or the related magnitude QRST integral8. The idea that voltage-derived variables, such as QRSAREA, should outperform QRS width in quantifying dyssynchrony and predicting CRT response is based on multiple assumptions, some biological and others methodological. The authors that developed and proposed these variables argued that the higher the voltage  the greater the amount of tissue with a delayed activation that results in unopposed electrical forces towards the end of ventricular depolarization22. In addition, voltage magnitude depends on cell viability, since cells from scar tissue do not develop action potentials and, therefore, QRSAREA could be inversely related to the amount of fibrotic tissue (which is not possible to resynchronize). QRSAREA is also sensitive to cell-to-cell electrical coupling, independently of the presence of conduction blocks23. Finally, while QRS width and classification widely depend on the specific criteria used and on the observer’s impression, the area under the curve of the voltage versus time plot relies much less on these variables. Together, these characteristics of QRSAREA make it a very good indicator of electrical synchrony and this magnitude has been proposed as a synchrony estimator for predicting CRT response with a performance better than QRS width alone, and just as good as the combination of QRS width and LBBB morphology7. However, the use of QRSAREA and similar estimators entails pitfalls that need to be addressed. First, there is no consensus on the QRSAREA cut-off value with best performance for quantifying dyssynchrony and predicting CRT response25. Second, there is also no clear agreement on which QRSAREA to measure, since most authors use 3D QRSAREA while others propose different quantities, such as QRSAREA over the Z axis or QRST integral26. Third, the use of the Kors-derived QRSAREA for predicting CRT response is largely based on small and medium-sized retrospective studies25. In these studies, cardiac mortality, overall mortality or combined end-points  are evaluated as primary and secondary outcomes. QRSAREA, analysed alternatively as a continuous or dichotomous variable using several different cut-off values , suggested a modest improvement  compared to QRS morphology and QRS duration, which were usually evaluated separately. Only one of these studies analysed the additional predictive value of QRSAREA on top of class I indication (with LBBB and QRS duration ≥ 150 ms), showing a moderate performance (HR 0.54 [0.41–0.70])7. Therefore, despite the great value of these studies, QRSAREA is far from being an ultimate solution to synchrony assessment, a fact that is reflected in its absence from clinical guidelines27.Currently, the best-known ventricular synchrony estimator is the QRS width. Along with QRS morphology, this is the only electrical synchrony estimator to be included in guideline recommendations for the indication of CRT in patients with heart failureAREA clearly contains more information on ventricular depolarization than QRS width, it lacks information on the temporal dynamics of ventricular depolarization. For instance, a narrow QRS with high voltage can have the same area under the curve as a wide QRS with low voltage. Hence, the advantages of using a magnitude such as QRSAREA could be potentiated by incorporating a variable that accounts for the time dynamics of ventricular depolarization. Our results indicate that this variable could be the vector speed.Finally, although QRS28, and our observation of a linear relationship between VTI and STI, we hypothesize that in physiological conditions tissue conduction is optimized to depolarize the entire ventricular mass in a very narrow time frame. Specifically, we speculate that this optimization probably involves the anatomical and electrophysiological properties of the heart’s conduction system, together with myocyte membrane channels, cytoplasm conductivity and intercellular gap junctions. We propose that for a given voltage there is a narrow range of optimal tissue conduction speeds, and that alterations in this relationship could indicate an electrophysiological impairment, which may lead to dyssynchrony and, ultimately, to mechanical impairment. In our study, the analysis of circa 100 control individuals allowed us to find a positive linear correlation between the ventricular depolarization STI and VTI from which we were able to extract the slope characterizing normal ventricular conduction. Following a similar approach, vector magnitude and speed from different conduction patterns were previously described in the 1960s in dogs and humans29, although no further attention was given to these curves, and no relationship between these variables was determined. To our knowledge, this is the first time that both vector magnitude and speed are included in the analysis of ventricular activation synchrony. Although the vector’s speed does not represent the speed of the depolarization wave itself, these are probably related since the vector’s speed derives from changes in the spatial angles and magnitudes of consecutive vectors13. Therefore, the inclusion of this variable in the analysis of ventricular activation synchrony could contribute to overcome the limitations of previous methods by taking into account tissue conduction properties, at least indirectly. Since in our study normal wavefront propagation is characterized by a linear relationship between voltage and speed, the quantification of the deviation from this line provided by our dyssynchrony index is likely to be independent of non synchrony-related variables such as the amount of cardiac mass and the electrical properties of non-cardiac intrathoracic tissue (i.e. volumetric conductor properties).Given the dependence of signal voltage on conducting tissue massThe voltage-speed time integral plot proposed in this study could be interpreted as a phase space, which is a popular representation for dynamic systems in Physics. In this space, there is a region near the control line where the probability of finding ventricular dyssynchrony is low. As the distance to the control line increases, this probability becomes higher. Just as an order parameter describes the transition between a solid and a liquid phase, our index would reflect the transition between a synchronous and a dyssynchronous phase of ventricular electrical conduction. The automatic analysis of a large ECG database of almost 2000 patients with a wide spectrum of ventricular conduction disorders allowed us to confirm that higher index values are found among patients with conduction abnormalities typically associated with dyssynchrony. Notably, the only paced patient with a dyssynchrony index close to control population values was a CRT user. These results led us to speculate that a clinically relevant threshold value for the dyssynchrony index would lie near 0.588, since this value adequately discriminates patients with LBBB or PM from the rest of the population Figs.  and S5. 30. The optimization of CRT configuration can be attempted by modifying atrio-ventricular activation time (AV synchrony), ventricular electrode positioning and ventricular activation time (intra and interventricular synchrony), depending on the device and electrode type. Much effort has been invested in developing tools and methods for establishing optimal device parameters. During the implantation, it is common to systematically place the LV lead in the posterolateral or lateral branch of the coronary sinus vein, since this region most frequently accounts for delayed activation. However, even in patients with LBBB, the posterolateral zone is not always the most dyssynchronous region31. There is evidence supporting the use of pre-procedure echocardiography to improve CRT outcomes by using speckle-tracking to identify the last LV region to be activated. However, the use of this technique in real-world scenarios is scarce since it is extremely time-consuming and due to lack of availability and expertise, among other causes33. In the operating room, intra procedure image-guided synchrony assessment is even more technically difficult. The electrically-guided placement of LV leads in the last site to be activated is a more feasible alternative that is being currently evaluated in clinical trials, although there is still no concluding evidence of a beneficial effect35. Regarding post-implant optimization, the same limitations described for pre-procedure evaluation also hold true. Implementation difficulties and lack of strong evidence of clinical benefit preclude post-implant optimization from forming part of routine practice36. These difficulties are even greater when using multipolar electrodes, since there are even more possible stimulation sequences available. In this scenario, we believe that a patient-specific and real-time approach would be crucial for device optimization.While inappropriate patient selection may account for a subgroup of CRT non-responders, another subgroup could be explained by sub-optimal catheter placement or device configuration. Regarding the latter, an appropriate device configuration can result in synchrony improvement, even if LV catheter implantation is not optimalOur results show that the dyssynchrony index proposed in this study is able to discriminate between different alterations in the ventricular depolarization sequence. Interestingly, patients with low (high) index values also had low (high) TPS-SD values, which is a proxy for mechanical dyssynchrony Fig. . This suThis study sets the basis for the potential use of a ventricular synchrony quantification tool in the scenario of CRT. As a limitation, although an important number of ECGs were analysed, only a small amount of patients actually had a resynchronization device: one from the local BH database and 10 in the echocardiography cohort . Hence, testing our computational pipeline in a larger population of patients with CRT devices will be key to further evaluate the method’s efficacy.The dyssynchrony index implemented in our computational pipeline has proven to be a promising tool for ventricular electrical synchrony evaluation, with potential applications within the framework of CRT during candidate patient selection, device implant, and post-implant optimization. Whether this index correlates with other mechanical and clinical outcomes will be the matter of future studies.12. The 49 controls from this database were included in a control population group, which also included the ECGs obtained prospectively from 41 local university students who were healthy volunteers with no history of cardiovascular pathology . ECGs from 1914 patients evaluated at the Hypertension Department of the British Hospital of Buenos Aires  between February and November 2019 were retrospectively analysed . ECG/echocardiogram recordings were obtained from 10 patients with PM or CRT devices during device optimization . Patient characteristics of this last group are described in Table This study was designed to test the ability of our newly developed dyssynchrony index to identify patients with impaired ventricular activation sequence, and to quantify the degree of this alteration. The study was an observational cross-sectional study that included multiple sources of ECGs Fig. : an onli12-lead ECG data were obtained using a digital electrocardiograph  connected to a personal computer with an acquisition software . Data sampled at 1000 Hz were stored as a “comma separated value” text file. Data analysis was executed by a custom software developed in MATLAB .11. The instantaneous vector magnitude (voltage(t)) at time t was calculated as:ECG recordings can be considered as 12 projections of a series of vectors that describe the electrical activity of the heart. The spatiotemporal trajectory of these vectors is denominated VCG. In this study, we developed a method to automatically extract VCGs from digitalized ECG signals. Briefly, through peak detection, polynomial fitting and numerical derivation, our algorithm detects a patient-specific voltage threshold. After processing, ventricular depolarization signal onset and stop were robustly detected  to finally obtain the patients’ VCG. Detailed description of each step is given below. Pre-filtered  data from the ECG machine were further filtered through a Butterworth filter. Drift and baseline wander correction was performed by subtracting a polynomial fit (10th order) to the original signal. Instantaneous values of the vector’s magnitude in the orthogonal planes  were obtained by the transformation matrix method described by Korsspeed(t)) at time t was calculated as:Spatial vector speed  and the voltage time integral (VTI) in the control population. We defined the dyssynchrony index as the shortest distance between the patient’s VTI-STI coordinates and the line obtained from the control population’s linear fit. Since the magnitudes on the abscissa and ordinate were different, we first normalized each unit to arbitrarily selected values  in order to nondimesionalize the data. Once the data were conveniently normalized, the dyssynchrony index of a patient with coordinates VTI and STI was calculated as:18. Briefly, DICOM images were imported to a commercially available software  which automatically performed LV segmentation into 18 segments  and endocardial surface detection. Time-strain data for all segments were exported to a commercially available spreadsheet program. Time to peak strain (starting from the onset of the QRS complex) for each of the 18 segments was detected to finally calculate TPS-SD.All echocardiographic studies were performed with an iE33 echography system equipped with a 3-MHz sector transducer . Grayscale 2D cine loops were obtained at the standard apical views . Mean frame rate was 61.6 ± 5.9 frames/s (mean ± SD). Mechanical dyssynchrony was assessed as the standard deviation of the time to minimum systolic strain 16:Differences among groups were evaluated by a Wilcoxon rank sum test, since data were non-normally distributed. In all cases, tests were two-sided and considered a 0.05 level of significance and 80% power. Sample sizes  were specifically stated in figures legends. The normality of data was evaluated by the Kolmogorov–Smirnov test. For establishing the cut-off value of the dyssynchrony index, a logistic regression analysis was performed and the dyssynchrony index value with the best discrimination ability between synchronous and dyssynchronous groups was selected using the highest Youden indexThe British Hospital of Buenos Aires’ institutional review board approved this study with a waiver of consent for ECGs retrospectively analysed, and with written informed consent required for ECGs/echocardiograms prospectively acquired during device optimization (protocol numbers 966 and 967). Informed consent was obtained from all participants prospectively enrolled. The study was conducted according to the principles of the Declaration of Helsinki (version 2013) and the International Conference on Harmonization Guidelines for Good Clinical Practice.Supplementary Figures.


The echocardiographic assessment of valvular heart diseases is the basic analysis of valvular defects next to clinical investigation and stethoscopy. Severity of mitral regurgitation (MR) is usually estimated by an integrated approach using semi quantitative parameters and is still one of the biggest challenges of echocardiography. Quantitative echocardiographic analysis of MR severity often fails to describe comprehensible hemodynamic conditions. However, comprehensive echocardiography based on standardized image acquisition and proper image quality is required to properly assess hemodynamic parameter comparable to cardiac magnetic resonance tomography. This review focuses on the uncertainty of MR severity assessed by echocardiography in recent trials of interventional MR treatment. In addition, the necessity to provide plausible echocardiographic data for individual decision making is highlighted. In conclusion, plausible functional diagnostics by rational echocardiography is a prerequisite in patients with valvular heart diseases. Echocardiography is usually the primary diagnostic procedure in suspected valvular heart disease (VHD) –4. ClariTMVR)—mainly by transcatheter edge-to-edge repair (TEER)—in functional or secondary MR (FMR) based on the characterization of FMR severity by echocardiography  leaflets.” and “In contrast, patients with EROA of 0.3–0.4 cm2 but a LVEDV of only 160–200 ml exhibit degrees of MR that are disproportionately higher than predicted by LVEDV. These patients appear to preferentially benefit from interventions directed at the mitral valve.”  of 75 ml. In the presence of a regurgitant fraction (RF) of 50% the effective stroke volume (LVSVeff) is 37.5 ml.A left ventricle with a left ventricular (LV) end diastolic volume (LVEDV) of 250 ml and a LV ejection fraction (LVEF) of 30% has a total LV stroke volume , a normal cardiac index (CI) is in the range from at least 2 to 2.2 l/min/m2, which results in a cardiac output (CO) of at least 3.8 l/min. There are no data about the CI-range in hemodynamically stable FMR patients. However, it can be assumed that the lowest CI in FMR patients might be ≤2 l/min/m2, presumably in the range from 1.7 to 2.0 l/min/m2.In case of a body surface area (BSA) of 1.9 meff is 37.5 ml, a heart rate of 86/min will be necessary to ensure a CI of 1.7 l/min/m2 (1700 ml x 1.9 m2/37.5 ml). Subsequently, a heart rate of 101/min will be necessary to ensure a CI of 2.0 l/min/m2 (2000 ml x 1.9 m2/37.5 ml). In contrast to these calculated heart rates the heart rates of HF patients with optimal medical treatment (OMT) are usually in ranges of 55–60/min.If LVSVtot is 48 ml and LVSVeff is 24 ml. Thus, a heart rate of 135/min is needed to obtain a CI of 1.7 l/min/m2 (1700 ml x 1.9 m2/24 ml), and a heart rate of 158/min to ensure a CI of 2.0 l/min/m2 (2000 ml x 1.9 m2 / 24 ml), respectively.According to the definition of a “disproportionate” FMR with a RF of 50%, a LVEDV of 160 ml and a LVEF of 30% LVSVIn conclusion, hemodynamics should be critically discussed and pose the question “whether hemodynamic considerations should be checked with respect to plausibility and should be integrated into the approach of assessing MR severity or not?” .tot can be determined by the addition of LVSVeff and the transmittal regurgitant volume (MRRegVol) during systole provided that LVEDV and LVEF are properly assessed. According to physical laws in communicating tubes proportionality always exists between volume flow and cross-sectional area (CSA) or between flow velocities and CSA. In echocardiography, it must be considered that spectral and color-coded Doppler signals represent blood flow velocities, not volume flow.“Disproportionate” FMR describes the disproportionateness between EROA and LVEDV –14. HoweRegVol in MR , VTIMAret is the velocity time integral of the systolic retrograde flow velocities determined at the MA level by pw Doppler and VTIMRret is velocity time integral of the systolic retrograde transmittal flow velocities determined by cw Doppler. However, it is not possible to perform these measurements to analyze EROA in MR patients like in AS patients due to the deceleration of retrograde transmittal flow velocities and the impossibility to assess high regurgitant flow velocities at the mitral annulus (MA) level by pw Doppler  in aortic valve stenosis (AS) by the continuity equation , 3, 5. Bol in MR . Thus, t Doppler , 16. HowRegVol by the 2D-PISA  method  the assessment of LV volumes , 2) the theRegVo) method , 6—and  by TTE—especially in comparison to cardiac magnetic resonance tomography (CMR)—is an ongoing debate , 20. A sV cavity , there a CMR see  as well  CMR see  are illu CMR see , approacAlthough it is not recommended to use the jet area for MR quantification and despite of the inappropriateness to quantify MR severity by its size and its relation to the left atrium, this approach is still the most often so-called semi quantitative parameter that is used for grading of MR severity . The secby 2D−PISA to avoid misunderstanding and misinterpretation  (The CSA of the left ventricular outflow tract (LVOT) is relatively stable and transvalvular flow velocities are integrated during systole, which is why the EOA of AS can be assumed as a relatively stable value, if certain measuring errors will be avoided. In contrast—especially in eccentric MR—the velocity time integral (VTI) of regurgitant flow velocities is difficult to delineate and the PISA-radius using the 2D-PISA method varies during systole. In primary MR often a late systolic regurgitation with a late time-to-peak-shape can be observed. In FMR the PISA-radius also varies during systole in many cases. Thus, variations of both parameters cause a wide range of measuring errors often resulting in overestimation of MRa (GROA) –24. The a (GROA) .RegVol) can be determined by the difference of LVSVtot and LVSVeff. Consecutively, EROA can be calculated by the equation MRRegVol/ VTIMR, whereas MRRegVol is defined as LVSVtot - LVSVeff, and not MRRegVol determined by 2D-PISA. However, the quantitative assessment of LVSVtot, LVSVeff, and MRRegVol requires a highly standardized and comprehensive echocardiography to ensure reliable, verifiable, and reproducible data  as presented in recent recommendations  the causal relationship of treatment effects can still be discussed.post-hoc analyses of inconclusive echocardiographic data (Thus, the current concepts of FMR quantification require validation preferably by data based on verifiable and transparent assessment of FMR severity by echocardiography , 24. Comhic data –14, 22 ahic data , 30 may Plausible functional diagnostics by echocardiography enables a conclusive and quantitative analysis of hemodynamics in VHD. The integrated approach to grade MR severity by semi quantitative parameters is often misleading. The main sources of errors by echocardiography include underestimation of LV volumes—mainly due to foreshortening and non-standardized views—and overestimation of regurgitant volumes and regurgitant fractions calculated by the 2D-PISA method due to several limitations. The hemodynamic assessment of FMR severity must be performed under comparable circumstances with OMT. Investigational circumstances must distinguish between life conditions the day prior to and after the intervention by TTE, and sedated conditions directly prior to and after device deployment by TEE. In all recent TMVR trials FMR severity can be assumed to be less than severe according to hemodynamics. Thus, due to the uncertainty of FMR severity the target of treatment remains unclear. The prevention of future LV decompensation after TEER treatment might by a more important issue than the treatment of a severe FMR. This hypothesis sets up the stage for further studies to determine the prognostic value of TMVR treatment.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Arrhythmogenic Cardiomyopathy (ACM) is a hereditary cardiomyopathy often presenting with sudden cardiac death (SCD) in young athletic individuals. Since it is a hereditary disease and alters the structural and electrical function of the heart, it is the focus of a large variety of scientific studies. The potpourri of clinical scenarios makes the name “arrhythmogenic cardiomyopathy” an umbrella term for different clinical conditions being characterized by structural cardiomyopathic changes and arrhythmias, mostly of ventricular nature.DSP), Filamin C (FLNC), Phospholamban (PLN), and Desmin (DES) [DSP, which accounted for half of the published cases, was the disease-causing gene with the highest frequency, followed by FLNC. An examination of the clinical characteristics of ALVC patients reveals significant electrical instability, which frequently necessitated an ICD implant . Most prevalent characteristic electrocardiogram (ECG) abnormalities were low peripheral QRS voltage and negative T waves in the lateral and inferior leads . Additionally, episodes of myocarditis were often observed . To better estimate the risk of SCD, compared to the 2015 International Task Force Consensus (ITFC) statement and the Heart Rhythm Society (HRS) criteria, the novel arrhythmogenic right ventricular cardiomyopathy (ARVC) ventricular arrhythmia (VAs) risk prediction model developed by Cadrin-Tourigny et al. was found to be more reliable at predicting sustained VAs in a primary prevention setting [ARVCrisk.com (accessed on 1 July 2022)) has been accessed >20,000 times illustrating that it responds to an unmet clinical need. Other independent groups have recently validated this risk calculator in their cohorts as recently carried out in a Chinese ARVC Cohort published by Zhang N et al. This rigorously conducted validation study published in this journal showed a good fitness for the prediction of arrhythmic risk [Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a distinct phenotypic form of ACM that has recently been described. It is characterized by predominantly left ventricular involvement with no or little right ventricular anomalies. In this type, several disease-causing genes have been discovered including Desmoplakin (in (DES) . DSP, whmic risk . The ARVAccording to the publication by Roudijk RW et al. clinicians should also consider 12-lead ECG indicators for the estimation of ventricular arrhythmic events in ACM patients. As highlighted by the authors one of those parameters, quantitative fragmented QRS (Q-fQRS), which is calculated by finding the number of positive and negative deflections in the QRS complexes on a 12-lead ECG, can be a warning sign of early-stage disease . Even ACDSP truncation type variants exhibited lower skin temperatures and higher transepidermal water loss, consistent microscopic cutaneous findings, and hair shaft involvement (pseudomonilethrix) with distinctive patterns such as the “fingerprint sign” [Skin abnormalities may aid for the diagnosis of ACM in specific patient groups in addition to ECG measurements and other clinical variables. In a recent innovative study by Cabrera-Borrego E et al. published in this journal, heterozygous patients with ACM and nt sign” . The autDSG2) mutant mice showed that these cells are more mobile and ready to mobilize to the injured region of the affected heart. This could be an important factor for myocardial remodeling and the development of fibro-fatty lesions in patients with ACM, as well as a novel approach to halting the progression of heart failure in ACM. Furthermore, cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have proven to be an effective In-vitro model for studying cardiac disease and have the potential to find possible therapeutic targets. A recently published study by Hawthorne RN et al. presented a hiPSC-CM model of ARVC obtained from a patient with a new pathogenic DSG2 variant (c.2358del (p.Asp787fs)), and showed an unique phenotype with altered DSG2 expression, increased inflammatory signaling and electrophysiological abnormalities in comparison to controls [An exciting translational study on Bone Marrow Mesenchymal Stromal Cells (MSCs) by Scalco A et al. raised the possibility that multicellular involvement may play a significant role in the pathophysiology of ACM . The exadel p.Asp87fs), anOn the other hand, it has been suggested that discontinuing competitive sports can slow the course of heart failure and lower arrhythmic occurrences in patients with ACM. In a recent study from Koch K et al., the exercise performance of ACM patients who did not discontinue with sports activity (the non-adherent group) regressed, and the left ventricular ejection fraction declined during the long-term, whereas both parameters remained stable in patients who stopped exercise activity (adherent group) . Based oACM patients are more susceptible to atrial arrhythmias due to atrial remodeling, atrial myopathy, and electrophysiological alterations at the cellular level that arise during the disease course. Although many atrial arrhythmias can be successfully treated with well-known catheter ablation (CA) techniques, there is a lack of evidence regarding the effectiveness and safety of such procedures in ACM patients. The most recent and largest systematic evaluation of the effectiveness and safety of CA for treating atrial arrhythmias in patients with ACM concluded that CA was a successful strategy for treating atrial arrhythmias including atrial tachycardias (AT), atrial fibrillation (AF) and typical atrial flutters in patients with ACM with low complication rates . During DSG2 mutant mice under emotional stress, but also deterioration of heart function, fibrosis, and adverse remodeling in surviving mice harboring this DSG2 mutation. Elucidating the pathogenic role of PSS as an environmental factor on patients with ACM in future studies may be important to tackle this challenging disease. In summary, this editorial summarizing recent important contributions published in the Journal of Clinical Medicine sheds light on the various aspects of translational and clinical research in ACM, from etiology and pathophysiological mechanisms to risk stratification, disease prevention and therapeutic potentials.Psychosocial stress (PSS) is another well-known risk factor but has lately received attention in the field of ACM . PSS may


Premature ventricular complex (PVC) is a frequent finding in the general population. The atrial conduction time (ACT) is the period between the electrocardiographic P wave and the atrial mechanical contraction, and its prolongation indicates an atrial electromechanical delay (EMD). In our study, we compared atrial conduction parameters by echocardiographic methods between patients with frequent PVC and healthy control subjects.The study included 54 patients with PVC and 54 healthy volunteers. Atrial conduction parameters were measured with echocardiographic examination. The time difference between the p wave and the Am wave was measured in the septal, lateral, and tricuspid annulus regions. The interatrial EMD, left atrial intra‐atrial delay, and the right atrial intra‐atrial delay were calculated from these measurements. The groups were compared for demographic and electrocardiographic features and echocardiographic parameters.p = .001, p < .001, p < .001, respectively). PA lateral, PA septal, and PA tricuspid durations were significantly prolonged in the patient group . All ACT parameters were significantly prolonged in patients with PVC QRS duration of 150 ms and above . All ACT parameters were prolonged in PVCs of right ventricular origin than those of left ventricular origin . ACT parameters were prolonged in patients with a coupling interval time below 485 ms .Left intra‐atrial EMD, right intra‐atrial EMD, and interatrial EMD were significantly longer in the patient group (Atrial conduction times are prolonged in patients with frequent PVC. While the pathophysiological mechanisms of PVCs remain mostly unknown, potential mechanisms include triggered activity, increased automaticity, and reentry. Advanced age, a taller height, a history of coronary heart disease, arterial hypertension, smoking, and decreased physical activity each predict a greater PVC frequency. A higher PVC frequency is associated with an increased risk of cardiovascular death, cardiomyopathy, and ischemic stroke.PVC most frequently affects ventricular function in structurally normal heart. PVC can also cause retrograde ventriculoatrial conduction. These retrograde atrial activations can affect cardiac conduction systems like atrial ectopies. Increased PVC frequency correlates with increased left atrial (LA) maximum volume.The atrial conduction time (ACT) represents the period between the electrocardiographic P wave and atrial mechanical contraction. The prolongation of ACT is termed the atrial electromechanical delay (EMD). Interatrial conduction times can be measured without invasive methods using Doppler and tissue Doppler imaging (TDI) in echocardiography.Prolonged ACT is associated with increased LA diameter and reduced LA function. It has been shown that left atrium negative remodeling may develop and LA diameter may increase in patients with frequent PVCs. Therefore prolonged ACT may be expected in patients with frequent PVCs.In this study, we compared atrial conduction parameters by echocardiographic methods between patients with frequent PVC and healthy control subjects.22.1Fifty‐four patients with more than 10 000 PVC observed over 24 h of ambulatory rhythm Holter monitoring and 54 healthy volunteers with comparable demographic characteristics were included in the study. Twenty‐four hours of ambulatory rhythm Holter monitoring revealed no arrhythmia in the control group. Patients with coronary artery disease reduced left ventricle ejection fraction (LVEF 50%), other arrhythmias , moderate and severe valvular heart disease, significant congenital heart disease, or left ventricle (LV) hypertrophy were excluded from the study. Since current literature does not suggest a cutoff value for frequent premature atrial contractions (PAC), we considered frequent PAC to be present similar to frequent PVC which was defined as more than 30 PVC in an hour.2.2We assessed resting electrocardiograms. PVCs were analyzed regarding the QRS duration, amplitude, and morphology. PVCs are classified with respect to the presumed chamber of origin. In general, the left bundle branch block (LBBB) morphology of PVCs originates from the right ventricle (RV) and RVOT, however, PVCs originating from the septal left ventricular outflow tract (LVOT) or aortic cusp may also have LBBB morphology. Right bundle branch block (RBBB) morphology represents left ventricular origin. To distinguish right ventricular outflow tract (RVOT) versus LVOT origin we used precordial transition of R wave (late vs. early). A QRS transition in the precordial leads later than that in sinus rhythm suggests an RVOT exit (and vice versa). If the QRS transition in both PVC and sinus beats is at V3, the “R wave transition ratio” can provide further guidance. When comparing the PVC R‐wave amplitude in V2 with that in sinus rhythm, a ratio ≥0.6 predicts a left‐sided origin. A coupling interval is defined as the interval measured from the onset of the R wave of the previous sinus beat to the onset of the PVC.2.3All participants were evaluated using the GE Vivid E95 system . Echocardiographic examination was performed within the first 24 h after rhythm Holter recordings were obtained. Single lead electrocardiography recording was acquired from all participants during echocardiographic assessment. The diameters of the left atrium (LA) and the LV were measured in accordance with the guidelines of the American Society of Echocardiography.2.4t‐test for continuous parametric variables, and Mann Whitney U test for continuous non‐parametric variables in group comparison. Univariate odds ratios (OR) were calculated for echocardiographic measurements associated with PVC and adjusted ORs were calculated controlling for other variables significant in univariate analysis. A p value of less than .05 was accepted as statistically significant.Statistical analysis was performed using IBM SPSS Statistics 22 software. Nominal variables are presented as numbers and percentages and continuous variables are presented as mean and standard deviation. The chi‐squared test or Fisher's exact test was applied for nominal variables, Student's 3In the study, there were 54 patients  and 54 control subjects  included. Table p < .001 and p < .001 respectively). Mitral A wave velocity and E/Em ratio, and LV systolic diameter were higher in the patient group . The remaining echocardiographic parameters did not differ between the patient and control groups.Table p = .001). PA lateral, PA septal, and PA tricuspid durations were significantly prolonged in the patient group (p < .001).Table Univariate OR was calculated for each conduction time interval. The effects of conduction time intervals on PVC were adjusted for gender, BMI, LVSD, LAD‐AP, A, and E/Em which were significant in univariate analysis. The studied conduction time intervals remained significant for the presence of PVC after adjustment and the ORs are presented in Table p < .001). It was observed that all ACT parameters were prolonged in PVCs of right ventricular origin than those of left ventricular origin . ACT parameters were prolonged in patients with a coupling interval time below 485 ms   was not performed for PVC evaluation and determination of origin. Many other common risk factors may lead to prolonged ACT in patients with PVCs such as older age and hypertension. Further study is necessary to understand these interactions clearly. Patients were not followed up in the long term for the onset of AF. Studies with a larger number of participants and longer follow up are needed to investigate the development of AF in patients with frequent PVC.6Atrial conduction times are prolonged in patients with frequent PVC.The work will be presented at the “European Society of Cardiology (ESC) Congress 2022, Barcelona” as an oral moderated poster presentation and will be published as an abstract in the supplement of the European Heart Journal.This study was approved by the ethics committee of the University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Turkey , and the research protocol followed the guidelines of the Declaration of Helsinki.All participants provided informed consent before participating in the study.


Sepsis is a leading cause of death and it is characterized not only by profound vasoplegia but also by myocardial dysfunction. Critical care echocardiography is the preferred modality for the initial assessment of the cause of shock. Moreover, it can be extremely helpful in the identification of progressing myocardial dysfunction during the course of sepsis, also known as septic cardiomyopathy.One of the issues in the identification of septic cardiomyopathy is that it can be manifest with different clinical phenotypes, from overt biventricular dysfunction to isolated left ventricular (LV) systolic and/or diastolic dysfunction, from right ventricular (RV) systolic dysfunction to RV failure and dilatation. However, the commonly used echocardiography parameters for the assessment of LV and/or RV function are not always entirely reliable. Indeed, these are influenced by variable preload and afterload conditions imposed by critical illness such as fluid shifts, sedation level and mechanical ventilation with positive pressure.Strain echocardiography is a promising tool for the early identification of myocardial dysfunction in the context of sepsis. Studies reporting data on strain echocardiography should be particularly detailed in order to increase the reproducibility of results and to favor comparison with future studies. Dear Editor,We read with interest the prospective study conducted by Bendary et al.  providinp = 0.52). The questionable impact of LV systolic dysfunction on outcome in sepsis has been previously confirmed by several meta-analyses [p = 0.03), which seems having a similar weight to the impact of RV dysfunction, Odds Ratio 2.01 . Although this finding points in the same direction of previous studies suggesting the important role of LV diastolic dysfunction in the outcome of critically ill patients [However, several results of this study deserve comments and clarifications. All together with an exhaustive CCE assessment, the authors  reportedanalyses –9. Convepatients , also inpatients , 13, it patients , 15. Thepatients , 17 to spatients . Howeverpatients , as recepatients –22.Other aspects of the work conducted by Bendary et al.  deservinPreferred Reporting Items for Critical care Echocardiography research Studies) recommendations [Finally, we may suggest the authors to adhere with the PRICES  but also on an extensive systematic literature appraisal , and pro


Inflammatory rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc), can cause cardiovascular complications in many cases. This study aimed to compare the ventricular and atrial functions of the heart between rheumatic patients and healthy controls using transthoracic echocardiography (TTE).P < 0.001). Left ventricular ejection fraction and right ventricular end-diastolic diameter were not statistically different between the groups (P > 0.05). Right ventricular septal strain, right ventricular free wall strain, average longitudinal right ventricular strain, tricuspid annular plane systolic excursion, right ventricular systolic myocardial velocity, and right ventricular fractional area change were lower in inflammatory rheumatic patients (P < 0.001). The subgroup analysis showed the same results’ trend for each disease and its own control group comparison.The study was performed between 64 patients with mentioned rheumatic diseases and 64 age- and sex-matched healthy controls who all underwent detailed history-taking and TTE. Echocardiographic parameters were measured and compared between the two groups. TTE showed significant differences in many echocardiographic parameters. Left ventricular end-diastolic diameter, left ventricular end-systolic diameter, right atrium area, inferior vena cava diameter, and systolic pulmonary artery pressure were significantly higher in patients compared to the controls (Cardiac involvement in rheumatologic diseases, especially SLE, RA, and SSc, should always be taken into consideration as there may be silent changes affecting the overall prognosis of patients. Using TTE helps diagnose and make a treatment plan for cardiovascular complications in rheumatic disease patients. Rheumatic diseases include but are not limited to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), vasculitis, systemic sclerosis (SSc), and spondyloarthropathies can cause several comorbidities, among which cardiovascular ones contribute the most to the mortality . These mTransthoracic echocardiogram (TTE), the most common type of echocardiogram, is a non-invasive, available, and accurate modality to investigate the heart’s structure and diagnose any dysfunction in it. Left ventricular ejection fraction (LVEF), the most common representative of left ventricle (LV) systolic function is mainly measured by TTE. In addition, other parameters represent other cardiac functions and may be used in combination to find a certain pathology . CardiacIn this case–control study, 64 patients with confirmed known inflammatory rheumatic diseases and 64 healthy individuals matched to the patients on the basis of age and sex referred to our institute were selected. All the patients selected were known cases of rheumatic inflammatory disease, including SSc, SLE, RA, or mixed connective tissue disease (MCTD) and none of them were in their flare episodes. All the controls were screened for rheumatic inflammatory diseases and were healthy. We excluded individuals with previous cardiac symptoms or known cardiovascular diseases and controls that used possibly confounding medication. Past medical history was taken from patients, including any chronic underlying diseases, smoking status, and drug history. This study was approved by the ethics committee of the Qom University of Medical Sciences (IR.MUQ.REC.1400.225) and informed consent was taken from all participants.An expert cardiologist measured the heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in both the patients and the control group. Height and weight were measured using common clinical devices by a research clinician. Body surface area (BSA) was reported according to the American Society of Echocardiography (ASE) as a commonly used metric for body size modification from weight and height using Boyd’s formula .TTE was performed according to standardized procedures for the patients and healthy individuals. The cardiologist interpreting echocardiograms was blinded to the group of participants. All procedure techniques and formulas were according to the ASE guidelines . LVEF, Lt-test was used to assess the significance of differences between inflammatory rheumatic patients and healthy individuals; and other analyses for continuous variables. The Chi-square test was used for categorical variables to calculate P value. Subgroup analyses were performed based on the rheumatic disease when possible. Statistical significance was considered a two-sided P value of less than 0.05 in analyses. All analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 26 .Continuous variables are presented as mean ± standard deviation (SD). The Student’s n = 30), SSc (n = 21), RA (n = 10), and MCTD (n = 3) in addition to 64 age- and sex-matched healthy individuals. The duration of rheumatic diseases was 36 [12–75] (median [interquartile range]) months. Four patients with hypothyroidism, three with anemia, and two with mild fatty liver were recognized upon history-taking. Smoking was seen only in two patients. Each group consisted of 11 males and 53 females. There was no significant difference between patients and controls in terms of SBP , DBP , and BSA . A significant difference between baseline HR was seen between patients and controls . Table We included 64 patients with inflammatory rheumatic diseases comprised of SLE . However, LVEDD, LVESD, and RA area were significantly higher in patients compared to the controls (P < 0.001). Moreover, there were significantly higher IVC diameter and PASP in patients compared to the controls . All other measures, including average longitudinal RV strain, TAPSE, RV systolic myocardial velocity, and RV fractional change area were significantly lower in patients compared to the controls (P < 0.001).The complete results of TTE are available in Table P = 0.152). In RA cases and controls, the RV-free wall strain and IVC diameter lost their significance .In rheumatic disease subgroups, the results were almost similar with minor differences. There was no significant difference in the RA area between SSc patients and their controls (12.67 ± 2.35 vs. 11.62 ± 2.29, In this study, we evaluated the atrial and ventricular function of inflammatory rheumatic disease patients and compared them with healthy controls. Almost all parameters in patients with rheumatic disease except LVEF and RVEDD significantly differed from the control group. Subgroup analyses showed cardiac involvement in each SLE, SSc, and RA group.Rheumatic diseases are responsible for myocardial, pericardial, valvular, electrical, and vascular changes in the cardiovascular system . IncreasSLE is an autoimmune disease that can affect various organs, including the cardiovascular system . It has Manifestations of SSc as another autoimmune disease are not limited to the skin, in a way that it can affect the whole body, including musculoskeletal, pulmonary, gastrointestinal, renal, endocrine, and cardiovascular systems . CardiacRA with a prevalence of about 1%, can have extra-articular presentations, including cardiovascular ones , 22. PerAlthough we did our best to make the study flawless, there were some limitations to our study. First, all the patients were selected from one center with the same ethnicity, which may threaten its generalizability. Second, despite highly-skilled cardiologists performing the TTE, this test is operator-related and may be erroneous in some cases. Finally, echocardiographic assessment in inflammatory rheumatic diseases has not been done much in the literature, and further research with more sample size is highly recommended.In conclusion, cardiac involvement in rheumatic diseases, especially SLE, SSc, and RA should always be considered as there may be silent changes in the heart affecting the overall prognosis of patients. Echocardiography is a safe and feasible tool for clinicians to diagnose and prevent such complications and reduce the total burden of the diseases.


Observational studies have demonstrated that treatment with sacubitril/valsartan may improve left ventricular (LV) systolic and diastolic function in subjects with reduced LV ejection fraction (LVEF) in real‐world studies. Subjects with heart failure and reduced EF (HFrEF), however, are also characterized by an impaired right ventricular (RV) function. We therefore aimed to evaluate whether also RV function may improve after S/V therapy and possible predictors of RV improvement could be identified at echocardiography and tissue Doppler imaging.Fifty consecutive patients  with chronic HFrEF and NYHA class II‐III were followed up for 6 months after therapy with S/V. LV&RV function was assessed at baseline and after 6 months of therapy.p < 0.001), TAPSE , RV FAC , RV S’ , RV‐FW‐LS , RV‐4Ch‐LS . At multivariable analysis improvement in RV‐FW‐LS was associated to baseline levels of RV S’  and RAV .After 6‐month therapy with S/V a significant improvement was shown in the following echocardiography parameters assessing RV function: PAsP (31 ± 11 vs. 35 ± 10 mmHg, In a real‐world scenario, 6‐month therapy with S/V was associated with an improved RV function in HFrEF. RV function improvement may be predicted by assessing baseline RV S’ and right atrial volume values. The presence of RV dysfunction indicates HF progression and may carry an additional worse prognostic value , and whether possible predictors of RV improvement could be identified.2Fifty consecutive patients with HFrEF in NYHA functional class II‐III, enrolled in the Daunia Heart Failure Registry as reported elsewhere  and late diastolic (A) LV filling, the ratio of trans‐mitral early to late (E/A ratio) LV filling velocity. LV dimensions and LVEF were calculated as recommendations in the joint ASE/ESC guidelines  was obtained by tracing along the endocardium of the LA in both relaxation and contraction phases, starting at the annulus, passing through the roof and ending back at the annulus in a four‐chamber view; these measurements were made according to the current accepted standard for 2D‐TTE LA volume measurement  was obtained by making a trace along the endocardium of the RV in both relaxation and contraction phases starting at the annulus, passing through apex and ending back at the annulus in a 4‐chamber view. FAC was calculated as (End‐Diastolic Area–End‐Systolic Area) × 100/(End‐Diastolic Area). Echocardiographic RA volume method included single plane Simpson's method of discs (Simpson's).The TAPSE was measured using apical views adjusted to optimize RV structures and to achieve proper orientation for M‐mode measures.Pulsed Doppler mitral inflow velocities were obtained by placing a 1–2 mm sample volume between the tips of the mitral leaflets in the apical four‐chamber view. The Doppler beam was aligned parallel to the flow direction. TDI measurements were recorded at the septal and lateral mitral annulus in apical four‐chamber view, included early (E’) diastolic velocities. Provision was made to average the peak lateral and septal velocities of the E’ wave. The averaged e’ was used for calculation of the E/e’ ratio .RV function was assessed using tricuspid annular plane systolic excursion (TAPSE), tissue Doppler velocity of the lateral tricuspid annulus (peak systolic velocity S’), RV FAC, Pulmonary Artery systolic Pressures (PAsP) values and RV speckle‐tracking strain imaging. The TAPSE was measured using apical views, adjusted to optimize RV structures and to achieve proper orientation for M‐mode measures.PAsP were estimated using the approach of calculating the systolic pressure gradient between right ventricle and right atrium by the maximum velocity of the tricuspid regurgitant jet, using the modified Bernoulli equation and then adding to this value the estimated right atrial pressures based on both sizes of the inferior vena cava and the change in calibre of this vessel with respiration, according to international recommendations. The peak tricuspid regurgitation velocity was assessed by placing the continuous Doppler through the tricuspid valve and the degree of tricuspid regurgitation was evaluated by the colour mode. Transthoracic echocardiography was performed using an EPIQ 7C ultrasound system  with X5‐1 matrix array transducer. All echocardiographic studies were performed and interpreted by experienced physicians, whom were blinded of clinical data.2.2Speckle‐tracking strain analysis was performed for each patient with the aid of a dedicated software (Qlab 10) to measure both RV‐FW‐LS and RV‐4ch‐LS. RV focused 4‐chamber view, with the Digital Imaging and Communications in Medicine (DICOM) formatted file images, were uploaded into a personal computer for subsequent off‐line GLS analysis with AutoStrain application. Longitudinal speckle‐tracking strain was calculated applying an automated contouring detection algorithm and regions of interest manual adjustments were performed where necessary. Based on the deformation of the green endocardial contour, longitudinal strain is computed for the free wall (RV‐FW‐LS) and the global 4‐chamber contour (RV‐4Ch‐LS) and was expressed as an absolute value in accordance with current guidelines.2.3t‐test, categorical variables as percentages and compared with χ2 test. Mean values were compared with Student's t‐test for paired groups. Linear correlations were determined by measuring the Pearson's correlation coefficient. Multivariable correction analysis was used to assess possible bias of confounders. A p < 0.05 was considered as statistically significant.Continuous variables were expressed as mean ± standard deviation and compared with Student's 2.4On the base of prior data indicating differences in the response of matched pairs with standard deviation 3.5 mm for TAPSE  are given in Table p < 0.001), indexed LV end‐diastolic volume , indexed LV end‐systolic volume , left atrium volume index ,LV function: LVEF , TAPSE , RV FAC , RV S’ , RV‐FW‐LS , RV‐4Ch‐LS  , baseline RAV max values , baseline RV S’ values , baseline TAPSE values  and baseline RV FAC values ; significant correlations with changes in RV 4ChLS were found with baseline right atrial area values , baseline RAV max values , baseline RV S’ values , baseline TAPSE values  and baseline RV FAC values   and RAV max , while changes in RV‐4Ch‐LS were associated to baseline levels of RV S’  and RAV max   frequently complicates HFrEF; S/V may increase levels of natriuretic peptides. The resulting action on natriuresis, diuresis and vasodilation may play an important role in the reduction of pulmonary pressures, thus affecting RV function.Our results are even more interesting, because there is evidence that RV recovery in patients with HFrEF is associated with improved survival  in HFrEF. Baseline RV S’ and right atrial volumes values are independent predictors of RV function improvement after 6‐month therapy with S/V.5.1Main limitations of the study are represented by the small number of patients enrolled, the monocentric and observational nature of the study; these preliminary results need to be confirmed in a properly powered multicentric study.The authors have no conflict of interest to disclose.Data are available on request.


Introduction: A substantial proportion of patients with adult congenital heart disease (ACHD) suffer from worsening valvular dysfunction in adulthood. Transcatheter valve interventions can offer a therapeutic alternative to surgery for those at high surgical risk. There is emerging but limited data on transcatheter interventions for atrioventricular (AV) valve dysfunction in patients with ACHD. Methods: We compiled an international collaborative multi-center registry focusing on adult patients with congenital heart disease undergoing transcatheter AV valve interventions (repair or replacement). Included were patients from three international centers who underwent procedures between 2016 and 2022. Demographic, clinical, and procedural data were compiled. Results: Nine patients with ACHD underwent AV valve interventions. The median age was 48 years , 55% women). At baseline, seven patients (78%) were in NYHA functional class III and two (22%) were in NYHA functional class II. The diagnosis of ACHD varied. Three valve interventions were performed on the subpulmonary AV valve and six on the systemic AV valve. The primary valvular pathology was regurgitation . Five procedures were valve-in-valve interventions, and four procedures were transcatheter edge-to-edge repair procedures. There were no major complications or peri-procedural complications or peri-procedural mortality. One patient developed a suspected non-obstructive thrombus on the valve that was medically treated. One patient did not improve clinically following the procedure and underwent a heart transplant, one patient died 6 months following the procedure due to a cardiovascular implantable electronic device infection. At one year, six patients were in NYHA functional class I, and one patient was in NYHA functional class III. In conclusion, transcatheter AV heart valve interventions are feasible and safe procedures in carefully selected ACHD patients. These procedures can offer an effective treatment option in these younger patients with high surgical risk. The prevalence of patients with congenital heart disease surviving into adulthood is increasing due to medical and surgical advances ,2. A sigWe compiled an international collaborative multi-center registry focusing on ACHD patients undergoing transcatheter AV heart valve interventions (repair or replacement). Included were patients from 3 international centers who underwent procedures between 2016 and 2022. Demographic, clinical, and procedural data were compiled. All patients were assessed in the setting of a local heart team and were favored for transcatheter management taking into consideration multiple parameters including anatomical complexity of the procedure, re-operative risk, etc.Descriptive statistics were used to tabulate and summarize baseline, procedural, and follow-up data. Categorical data are presented as numbers and percentages of the total; continuous variables are shown as means with standard deviations or medians with 25th and 75th percentiles  for non-normally distributed data. This project received ethics board approval.Included were nine patients with ACHD who underwent AV valve interventions. The median age was 48 years , 55% women). At baseline, seven patients (78%) were in NYHA functional class III, and two (22%) were in NYHA functional class II. The diagnosis of ACHD varied, as shown in A female patient in her sixth decade of life had a past history of primary lesion of a discrete sub-aortic membrane that had been resected and an ensuing Ross–Konno procedure and tricuspid valve replacement in her fifth decade of life due to severe tricuspid regurgitation with implantation of an Epic 33 mm valve. She was sent for AV valve intervention due to tricuspid bioprosthesis failure with severe regurgitation and stenosis. The patient had significant clinical signs of peripheral congestion with ascites and evidence of liver congestion on laboratory findings and was clinically in NYHA class III. On echocardiogram evaluation, the peak tricuspid valve pressure was 18 mmHg with a mean of 13 mmHg. The inferior vena cava was enlarged to 35 mm and did not undergo respiratory variation. Left and right ventricular systolic function were normal with a left ventricular ejection fraction of 60% and TAPSE 22 mm. The case was discussed in the heart team forum, and the patient was referred for tricuspid valve-in-valve (VIV) intervention, which was performed under conscious sedation via femoral vein access. A Sapien 3 29 mm  valve was inserted with a reduction in the peak tricuspid gradient to 6 mmHg and a mean gradient of 4 mmHg, as shown in ®  septal occluder device 13.5 mm was inserted at the end of the procedure. This can be seen in A female patient with congenitally corrected transposition of the great arteries had previously undergone replacement of the systemic AV valve with a Carpentier Edwards 25 mm bioprosthesis. She presented in the fourth decade of life with acute decompensated heart failure with severe structural deterioration of the bioprosthesis with mixed pathology of regurgitation and stenosis. On echocardiographic examination, the systemic ventricle had preserved systolic function, and the bioprosthetic valve had severe stenosis with a gradient of peak 45 mmHg with a mean of 20 mmHg as well as a flail leaflet with severe regurgitation. A Sapien 3 26 mm valve was inserted via femoral vein/transseptal access with hemodynamic improvement and residual minimal regurgitation and prosthetic patient mismatch with mild–moderate stenosis with an 8 mmHg mean pressure gradient. Due to a significant left-to-right shunt via the iatrogenic atrial septal defect and subsequent desaturation, an OcclutechA female patient was known with Ebstein anomaly, after mechanical tricuspid valve replacement in childhood and subsequent atrioventricular block with the need for a pacemaker. The patient previously had a non-obstructive stuck valve during pregnancy and had repeat surgery with the insertion of a 31 mm Hancock bioprosthesis 23 years prior to presentation. She presented in the fourth decade of life with valve structural deterioration with mixed moderate regurgitation, and stenosis with a mean gradient of 10 mmHg. The patient was referred for VIV intervention. The procedure was performed via femoral vein access with implantation of a Sapien 3 29 mm valve with no residual regurgitation and mean gradient of 2 mmHg. This is shown in A man in his sixth decade of life had a primary complex cyanotic cardiac defect of the double outlet right ventricle with pulmonary stenosis and underwent a Rastelli repair operation during his youth with the need for an epicardial pacemaker due to symptomatic bradycardia. He previously had a surgery in which a pulmonary homograft was implanted, the tricuspid valve was repaired, and a residual ventricular septal defect was closed. In the following years, the patient suffered from episodes of ventricular tachycardia, and the functioning of the tricuspid valve deteriorated and was replaced with a Hancock 33 mm bioprosthesis. The tricuspid underwent structural valve deterioration with mixed pathology of stenosis and regurgitation and, due to the accelerated valvular deterioration, anticoagulation therapy was initiated. The patient suffered from right heart failure with severe hypoalbuminemia from protein-losing enteropathy. The tricuspid valve underwent structural deterioration with severe tricuspid regurgitation. The echocardiographic assessment showed severe tricuspid regurgitation with vena contracta of 8 mm, an AV valve peak gradient of 8 mmHg, and a mean of 6 mmHg and an estimated systolic pulmonary artery pressure of 73 mmHg. The patient was referred for a tricuspid valve-in-a valve procedure. The procedure was performed via femoral vein access, and a Sapien 3 valve of 29 mm was inserted into the tricuspid bioprosthesis . The AV TM device. This reduced the mitral regurgitation to mild with moderate pulmonary hypertension. However, the patient remained clinically in NYHA functional class III and, one year later, underwent a heart transplant.This patient was in his second decade of life with idiopathic dilated cardiomyopathy from a young age with severe left ventricular dysfunction. He had significant heart failure, and his baseline NYHA function class was grade III and a known ejection fraction <30%. He had severe secondary mitral regurgitation with peak pulmonary artery pressure measured as 75 mmHg. A transcatheter edge-to-edge repair of the mitral valve was performed using a MitraclipA female patient in her eighth decade of life had cor triatriatum sinister Löffler III and concomitant severe mitral regurgitation. She was in symptomatic heart failure in NYHA functional class III.On echocardiography, she had a preserved ejection fraction with severe mitral regurgitation. She was referred for transcatheter edge-to-edge mitral valve repair with a Mitraclip™ device. On echocardiography following the procedure, the mitral regurgitation was reduced to mild with mild mitral stenosis and an increase in systolic pulmonary artery pressure from 17 to 37 mmHg.® Mitral Contour System®  12–20–60 mm. A vascular complication of a femoral pseudoaneurysm occurred during the procedure that was treated with thrombin injection. Following the procedure, the mitral regurgitation was reduced to moderate with no mitral stenosis and systolic pulmonary artery pressure decreased from 58 to 31 mmHg.A man in seventh decade of life with known atrial septal defect (ASD) with total pulmonary vein confluence previously underwent surgery with insertion of an ASD patch and implantation of a 28 mm Starflex-Occluder due to a residual shunt. He presented with severe mitral regurgitation and underwent transcatheter indirect mitral valve banding with Carillon2. The patient contracted CCOVID-19, which worsened heart failure symptoms. He was stabilized on heart failure medication and subsequently underwent a cardiac MRI, which showed a reduced EF of 35%, end diastolic volume of the systemic (right ventricle) of 198 mL/m2, and moderate-to-severe systemic AV valve regurgitation with regurgitant fraction of 38%. The patient remained in NYHA functional class III despite optimal medication therapy and was referred for the Mitraclip ™ procedure. The procedure was conducted via femoral vein access with puncture from the pulmonary to systemic venous baffle. Under TEE guidance, the tricuspid valve was seen with two leaflets only (anterior and posterior). Two Mitraclip™ XT clips were placed between the anterior and posterior leaflets, with assistance of the Triclip™ systemic for flexibility. At the end of the procedure, an iatrogenic atrial septal defect of 5 by 7 mm was found, and this was closed by an Amplatzer Flex II 10.5 mm occluder device. The systemic AV regurgitation was reduced to minimal with a mean AV valve gradient of 4 mmHg. One month following the procedure, the patient presented with heart failure and atrial flutter. This improved following cardioversion to sinus rhythm.A male patient in his fourth decade of life was born with D transposition of the great arteries and underwent Senning atrial switch operation as a child. The patient developed moderate-to-severe systemic AV regurgitation with mildly reduced function of the systemic (right) ventricle. He remained clinically stable over the years and underwent cardiac MRI that showed moderate tricuspid regurgitation with an ejection fraction of the systemic ventricle of 41% and an end diastolic volume of 166 mL/m2, pulmonary hypertension with PVR 8.6 Woods, and mitral valve area calculated to 1.3 cm2). Following a heart team discussion, it was decided that the mixed valvular dysfunction was significant, and a valve-in-valve procedure was performed under general anesthesia with a trans-septal approach with the implantation of a Sapien S3 26 mm valve. Balloon dilation was performed following the implantation. The TEE assessment following the implantation showed that the valve gradients were reduced to a peak of 9 mmHg and a mean of 5 mmHg. During the admission following the procedure, there was a concern that there was non-obstructive thrombus on the valve, and oral anticoagulation was changed to warfarin therapy. Following the procedure, the ventricular function did not improve. However, at the 6-month follow up, the patient reported a subjective improvement and was clinically stable on heart failure medications.A female patient in her fifth decade of life had congenitally corrected transposition of the great vessels. She had undergone systemic valve replacement with a mechanical valve in her youth, which was replaced with a biological valve (Hancock 25 mm) following valve thrombosis. The patient also had a pacemaker inserted due to complete atrioventricular block in her youth, and this had been replaced by a cardiac resynchronization device with an epicardial lead. She had been medically managed for atrial arrythmias. The patient developed symptoms of decompensated heart failure and underwent evaluation. On transesophageal echocardiography, the regurgitation was intra-valvular and graded as moderate to severe with a pressure gradient of peak 22 mmHg and a mean gradient of 6 mmHg over the bioprosthesis in the presence of severe systolic systemic ventricular dysfunction. A hemodynamic catheterization demonstrated postcapillary pulmonary hypertension with mixed valvular dysfunction  [Transcatheter tricuspid valve-in-valve has been shown to be an attractive treatment option in patients with Ebstein anomaly and a failing tricuspid bioprosthesis. Taggart et al. reported on 81 patients who underwent transcatheter tricuspid valve-in-valve implantation with an average follow up of 13 months. The majority had an improvement in functional class, and valve hemodynamics was improved. On subgroup analysis, they found that patients 19 to 40 years old had significantly shorter freedom from reintervention or valve dysfunction with an odds ratio of 8.02 (Our case series details a heterogenous patient population. ACHD is an umbrella term for multiple different pathologies. As described in our case series, each patient had different anatomical complexities that had to be treated innovatively. These cases were treated at tertiary centers with multidisciplinary teams with expertise in ACHD, imaging, and interventional cardiology. All cases were discussed with a heart team prior to intervention.Our data have some important limitations. The main limitation is that of the small number of patients in this case series of unique patients. Each patient had different pathology and valve disease. Our results cannot be generalized to the broader ACHD population. Data regarding the nature of the initial congenital diagnosis and prior interventions from childhood were limited or lacking in most cases.In conclusion, trans-catheter AV heart valve interventions are feasible and safe procedures in carefully selected ACHD patients. These procedures can offer an effective treatment option in these younger patients with high surgical risk and complex valvular lesions.