The tricuspid valve is a complex structure with normal function dependent on the leaflet morphology, right atrial and annular dynamics, and right ventricular and chordal support. Thus, the pathophysiology of tricuspid regurgitation (TR) is equally complex and current medical and surgical management options are limited. Transcatheter devices are currently being investigated as possible treatment options with lower morbidity and mortality than open surgical procedures. These devices can be divided by their implant location/mechanism of action: leaflet approximation devices, annuloplasty devices, orthotopic valve implants, and heterotopic valve implants. The current review will discuss each class of transcatheter device therapy, and further delve into the current understanding of who and when to treat. Finally, we will include a brief discussion of the future of device and surgical therapy trials for TR and the remaining questions to answer about this complex disease process. Severe tricuspid regurgitation (TR) is associated with significant morbidity and reduced life expectancy , 2 that Transcatheter tricuspid valve interventions (TTVI) have the potential for reducing the acute procedural and in-hospital adverse outcomes associated with cardiac surgery. Given the large underserved patient population and early reports of safe and effective outcomes after TTVI, there has been rapid development of devices to treat TR. Whether TTVI will improve survival compared to medical therapy may be answered in the randomized control trials currently enrolling. This review aims to outline the current understanding of TR etiology and its associated cardiac morphology, options for TTVI including device-specific characteristics and the required pre-procedural evaluation, as well as considerations for device choice. Finally, available TTVI outcomes data may offer a glimpse into what we can expect from the current pivotal trials.Historically the etiology of TR has been simplistically divided into primary  and secondary  however our current etiologic classification now reflects a more comprehensive understanding of the morphologic differences not only of the leaflets, but of the right atrial (RA) and right ventricular (RV) anatomy , 8. PrimUnderstanding the mechanism of TR is important when considering the best transcatheter treatment options given the various anchoring mechanisms and methods of action for each device. For example, transcatheter edge-to-edge repair (TEER) or annular repair devices will likely not eliminate CIED-related TR whereas replacement devices may be effective. TR related to significant leaflet tethering seen with ventricular secondary TR may not respond to an isolated annular device although TEER devices can result in significant TR reduction. TV leaflet variability  has receThorough pre-procedural imaging with cardiac computed tomography (CCT) and both transthoracic (TTE) and transesophageal echocardiography (TEE) allow for more specific pre-procedural planning with strengths and weaknesses of each modality. Importantly, TR varies not only with respiratory cycle and rhythm, but also with volume status. Thus irrespective of the imaging method, the assessment of disease severity should be performed under stable, optimal guideline directed medical therapy. New guidelines describe the utility of pre-procedural echocardiography for determining the location and size of the regurgitant orifice (and thus TR severity), evaluating leaflet and ventricular morphology (and thus TR etiology), assessing RV and left ventricular size and function, and determining the severity of concomitant valvular disease or other cardiac abnormalities . Due to Because patients present late in the disease process, five-grade TR severity scale  expands CCT is essential for the evaluation of annular size, CIED lead course, right coronary artery proximity and sub-valvular structures . CCT is also essential for the determination of appropriate access: venous access site dimensions and tortuosity as well as caval anatomy and approach to the tricuspid valve. A three dimensional (3D) understanding of vena caval course and angulation is important for guide-catheter positioning to allow for coaxial approach. The inferior vena caval to tricuspid annulus relationship  is highlBeyond anatomical considerations, a comprehensive understanding of physiological loading conditions is important in patient selection and outlook with valve intervention. This encompasses the conditions faced by the right ventricle and may help better understand the contribution of left-sided ventricular or valvular disease and PHT to best evaluate the likely benefit and safety of TV intervention. A multi-modal evaluation that utilizes non-invasive and invasive investigations to best quantify RV size and function, PA pressures, left heart hemodynamics and pulmonary vascular resistance should be performed, ideally in a euvolemic state.The RV has long been thought to be sensitive to afterload. Recent studies suggest that a PA pressure of ≥36 mm Hg, left atrial dilatation, age and atrial fibrillation are strong predictors of TR progression . ChronicBaseline reduced RV function has been associated with poor outcomes following isolated surgical interventions . MeasureInvasive measures of arterial afterload also has an important role in management decisions for patients with TR. Right heart catheterisation is essential to determine pre- versus post-capillary PHT, transpulmonary pressures and pulmonary vascular resistance, and right atrial pressures . DiffereOther baseline clinical parameters that may help to predict outcomes after TTVI include kidney and liver function . Cardio-TR is a dynamic condition that, depending on its mechanism, varies depending on loading conditions related to volume status. A volume-overloaded patient will result in a more dilated tricuspid annulus, more leaflet tethering and a broader coaptation gap. Performing TEE or CCT imaging evaluation in this state will reduce the likelihood of suitability for some if not all therapies. In many patients, admission for volume optimisation under the care of a multidisciplinary Heart Team, often spearheaded by an advanced heart failure service, is vital both in the evaluation phase and again pre-procedure. This “pre-habilitation,” often further guided by invasive right heart catheterisation hemodynamics, should increase likelihood of meeting anatomical criteria required for device intervention and assist with procedural success. “Pre-habilitation” should be strongly considered for any patient both prior to evaluation for intervention and again in the days prior to their procedure.TTVI for TR require careful selection relating to valve anatomy, mechanism of TR, presence of CIED related disease and right heart size and function. These considerations guide therapeutic strategy, repair, or replacement, with techniques that emanate from surgical repair such as leaflet approximation, direct annuloplasty and orthotopic or heterotopic valve replacement . A propoThese techniques include leaflet approximation  and annuloplasty devices. Current clinical data of these therapies are summarized in Tricuspid TEER is the most utilized device worldwide, with the initial off-label use of the MitraClip system  before the development and CE mark approval of the PASCAL  and TriClip  devices. Detailed pre-procedure TEE evaluation of the mentioned valve characteristics can assist with determining procedural suitability and likelihood of success using edge-to-edge repair techniques.TV leaflet morphology, number, and location , influenOther considerations that may influence patient selection for the TEER devices include baseline RV dysfunction, CIED related TR and contraindication for anticoagulation. Because an increase in RV afterload following TTVI is directly related to the amount of TR reduction the TEER devices may offer some advantages to the patients with baseline severe RV dysfunction where more modest TR reduction may not result in abrupt increases in afterload. However, this remains a theoretical advantage since no data supports differences in RV function following different devices. CIED leads can interfere with leaflet approximation and reduce TEER efficacy in cases where the lead is impinging on the leaflet and directly causative of regurgitation. In such scenarios, it is reasonable to consider lead removal/revision and an alternate CIED such as coronary sinus lead implantation or leadless devices . Unfortunately, the effectively of lead removal remains questionable and likely related to the duration of implantation, and the actual mechanism of lead impingement , 50. Onevia the common femoral vein and IVC over a guidewire. The TriClip delivery system is made up of a delivery catheter and an implantable clip that varies in size by length and width as used in MitraClip procedures; NT (standard length and width), NT-W (extra wide), XT (extra long) and XT-W (extra long and wide). An individualized approach is used to determine the appropriate device size.TriClip guide catheter is different from the MitraClip, having septal to lateral motion capability and a shorter guide curve. TriClip (Abbott Vascular) edge-to-edge repair is routinely performed under general anesthesia and TEE-guided with 24Fr guide sheath and introducer inserted In the TRILUMINATE trial of 85 patients evaluated at one-year follow-up, TR severity was reduced by at least one grade in 86% of patients . ModeratThe PASCAL repair system (Edwards Lifesciences) includes a 22Fr transfemoral guide sheath with a device consisting of a central spacer connected to two broad paddles with independently moving clasps. The device is made of nitinol, and uses a passive closure system that may reduce leaflet injury and stress. The PASCAL delivery system and device are the same for both mitral and tricuspid TEER procedures. The central spacer is helpful in occupying the regurgitation orifice and reducing leaflet stress. The newer PASCAL Ace implant features a narrower and shorter profile with longer clasps compared with the original PASCAL implant, all tailored to manage complexities of tricuspid repair; notably large TV annulus, dense chordae structures and wide coaptation gaps. In scenarios where the repositioning above the leaflets is desired, the device it can be elongated and retracted across the valve without leaflet/subvalvular injury or entanglement.The early feasibility CLASP TR study demonstrated safe profile with 85% TR reduction of at least one grade in 29 patients who had successful implantation . Five otThis spiral-shaped nitinol device improves leaflet apposition by gathering targeted chordae together atraumatically, forming a “flower bouquet” shape that reduces the coaptation gap through chordae and leaflet approximation. This transfemoral procedure involves an 8.5Fr steerable sheath that directs a delivery system with the Mistral device  into the RV. The device comes in either 8.8 mm outer diameter or a 7.4 mm outer diameter with both the same inner diameter of 5 mm. It engages leaflet chordae at the level between papillary muscles and leaflet tips and is rotated clockwise for a total of five full circles. This can be undone by reversing rotation to optimise chordae grasp. Stability tests are done throughout the various intervals of the procedure including before deployment.Seven cases are reported with procedure time 58 to 125 min. All procedures were successful with 30-day outcomes demonstrating significant TR reduction, symptomatic benefit and no adverse events .Annuloplasty, a common additive intervention for patients requiring cardiac surgery, is yet to establish itself as a transcatheter therapy. Being an annular treatment, it conceptually addresses the pathology of functional TR due to annular dilatation more so than leaflet approximation. To achieve surgical-like annuloplasty results, most transcatheter devices extend from anteroseptal to posteroseptal commissures to form an incomplete ring that spares the septal leaflet and atrioventricular node. This addresses annular dilatation in the anteroposterior direction which is what occurs in functional TR. Additionally, annuloplasty has the benefit of preserving native anatomy, allowing for future intervention with leaflet modification or valve replacement and does not require anticoagulation. Transcatheter annuloplasty systems can be grouped into ring (direct or indirect), suture and non-suture-based devices.Overall, there appears to be adequate procedural safety and efficacy in early feasibility studies but there are several notable procedural challenges and novel complications. Procedural imaging is again crucial and can be difficult in these procedures. Many direct annuloplasty devices require sequential annular anchoring, a meticulous and time-consuming process that when combined with difficult imaging, results in very long procedural times averaging nearly 5 hours . ImpingeThe first generation Cardioband Tricuspid Repair System (Edwards Lifesciences) is a direct, sutureless, and adjustable surgical-like Dacron band based on the mitral valve system. Guided by TEE (and ICE when required), an implant catheter is inserted through a 24Fr transfemoral access sheath and rested on the atrial side of the tricuspid annulus, where up to 17 anchors are deployed on the atrial side along the anterior annulus from the anterolateral commissure to the posteroseptal region. The band is sized according to pre-procedural CT measurements, with five different sizes dictating the overall number of anchors. For safety, a guidewire is placed down the RCA to provide a fluoroscopic landmark of its course. At each anchor implant, position should be carefully confirmed on echocardiography with a pull test to ensure secure insertion. Once all anchors are deployed, the implant delivery system is detached from the band and removed. The retained wire is then used to pass the size adjustment tool that attaches to the spool. Bidirectional reshaping of the annulus is then possible using the pre-mounted contraction wire that is connected to the adjusting spool. The device is then cinched in a controlled fashion with live visualisation of annular reduction and TR improvement. The band is contracted between 3.5–5.5 mm depending on size and echocardiographic findings. Then the device is released and the system is removed.The six-month and then two-year outcomes of the first-in-human prospective trial were reported totalling 30 patients , 59. TheThe DaVingi TR system  is a direct annuloplasty system that is implanted in two stages. An annuloplasty ring is passed through a 22Fr catheter from the jugular vein and positioned on the annulus from the atrial aspect. Anchors fix this to the annulus by being simultaneously fired. An adjustment connector is left fixed to the jugular vein and, 3 months later when the ring has healed, a second procedure is done to contract the annular ring size. This study is still recruiting with successful first-in-human experience published .via a right atrial appendage puncture. An adjustable lasso-like implant is opened and loops around the apex of the heart until it rests within the atrioventricular groove. Then the delivery system is removed and the device is tightened using a sliding Roeder knot, exerting external pressure at the tricuspid and mitral annular level. The right atrial appendage puncture is then closed using a nitinol occluder. A study in 16 swine demonstrated significant TV geometry changes (reductions in annular area and perimeter with improved TV coaptation) with minimal impact on the mitral annular geometry and hemodynamics  technology  consists of low-mass, polymeric, self-tensioning PolyCor anchors and the thermoplastic MyoLast polymer for tensioning of the anchors. A series of PolyCor anchors are placed along the posterior annulus and tension is applied to the attached suture which is then locked, plicating the annular tissue. Surgical feasibility in three patients was proven in the Study of Transcatheter Tricuspid Annular Repair (STTAR) trial with good safety and mean 43% reduction in tricuspid annulus area achieved .The 12Fr transcatheter system is under trial currently with initial 31-patient experience presented demonstrating reduction in annular area and TR grade as well as improved quality of life with a 10% pericardial effusion rate but otherwise good safety outcomes .This is another pledget-assisted suture tricuspid annuloplasty (PASTA) technique that involves traversing both the septal to lateral annulus and exchanging for two pledgeted sutures, each with two insertions to maximise force as a point of difference. Approach is transjugular with a deflectable catheter just like TriAlign or alternately can be transapical. The sutures are then tightened using a Cor-Knot device (LSI Solutions). Feasibility has been shown in 22 pigs . The douvia an additional jugular venous access. Then, pledgets are secured with Cor-knot to create double valve orifice and reduce TR. This has been performed in humans but no literature has been published as yet  involves an outer deflectable sheath that is placed in the right atrium and through this, an inner deflectable sheath with a clip is inserted. The clip has a central corkscrew which is screwed into the annulus to a max depth of 4 mm in a position that is parallel to the annulus, between the leaflets and a wire-protected RCA, and aiming towards the anteroposterior commissure. Then the clip is deployed, shortening the circumference of the tricuspid annulus whilst ensuring no coronary stenosis with selective angiography. The clip is then released and sheaths withdrawn. In 18 pigs, there was 100% procedural success with significant annular area reduction and without major complication . ProceduThese devices are designed around placement of a central spacer that enhances leaflet coaptation and reduces the regurgitant orifice area. The spacer is attached to a second component, either an anchoring caval stent or an anchor secured within the heart. The perceived benefits of this device type include that they can accommodate a large range of annular sizes and extreme coaptation gaps, a current limitation of most transcatheter tricuspid interventions. They also avoid direct interaction with annular structures, may not require complex imaging and may have short device times when compared to other types. However, this would not allow for re-intervention and more clinical outcome data is still required.CroiValve DUO  is a coaptation spacer valve attached to a superior vena cava (SVC) stent anchor system that has fewer anatomical contraindications with a single size of valve and delivery system for all anatomy. The system is delivered from the internal jugular vein with an adjustable, steerable catheter. The spacer is anchored to a deployed SVC stent and is not in contact with the tricuspid annulus or nearby cardiac structures. It may accommodate anatomical variability and very large annular sizes up to 65 mm. It is planned for further human testing this year.Tripair  consists of a central spacer with a flexible center column attached to an atraumatic right atrial crown that rests in the right atrium. This is implanted transfemorally, can be deployed quickly without complex imaging and is fully retrievable. It has yet to be used in humans.TTVR is establishing itself as a less-invasive valve replacement that, unlike leaflet approximation and annuloplasty, aims to abolish TR. Technical considerations relate to mechanism of anchoring (leaflets vs. annulus vs. chords), annulus shape/size, delivery approach and IVC course to the annulus. Replacement may theoretically be harmful in certain patients with poor RV reserve however how to measure RV function and reserve are areas of continued research. The IVC approach and angulation relative to the tricuspid annulus can influence device delivery, limit coaxiality and impact procedural success. Different TTVR systems have different anchoring mechanisms and thus different imaging requirements. In general, these intraprocedural imaging requirement are less for TTVR than for leaflet approximation or annular devices.The device characteristics and mechanisms of deployment are discussed in The EVOQUE system (Edwards Lifesciences) is a 28Fr transfemoral venous system which can allow for a 44 mm, 48 mm or 52 mm diameter valve implant. The delivery system is capable of primary and secondary flexion as well as adjustable depth. The valve is made of bovine pericardium, is trileaflet, has a nitinol frame with nine anchors and a fabric skirt. After positioning of a pre-shaped guidewire carefully toward the RV apex and in a central position across the TV, the delivery system is advanced to the RA where it is flexed across the TV. After advancement of the delivery capsule below the valve, position and trajectory are optimised and anchors are exposed below the leaflets but above the papillary muscle heads. Then as the valve is exposed and expands, the anchor tips become positioned subannular to capture the leaflets. When there is adequate leaflet capture and positioning below the annulus, the valve is fully deployed and released, with careful system removal without interaction with the valve.The TRISCEND study  30-day results of 56 patients demonstrated mild or less TR in 98% with improvement in NYHA class, 6MWD and Kansas City Cardiomyopathy Questionnaire . Median via mini right thoracotomy or transatrial approach and is radial force-independent unlike other TTVR devices. This is designed to minimise force-related complications of conduction disturbance and RCA impingement but may be at a trade-off for increased risk of paravalvular regurgitation.The LuX valve  is a 32Fr flexible delivery system with a bovine pericardial valve on a nitinol valve stent that has an atrial disc, an interventricular septal anchor “tongue” and two expanded polytetrafluoroethylene-covered graspers. It has four valve sizes (30 to 55 mm) and eight disc sizes to treat annular diameters of 25 to 50 mm. It is delivered Procedural success was achieved in 45 of 46 cases with one fatal RV perforation. Mean procedure time was 150 min. 33 patients achieved none or mild TR at six months follow-up .via transjugular approach via a 30Fr sheath. It is collapsible and repositionable until the fixation arms are fully expanded. It can be used in a septal-lateral annular diameter of 40 to 53 mm. There is one published case report of its successful use  is a bovine pericardial monoleaflet valve attached to two commissures to create a bicuspid prosthesis. This is mounted on a thin, self-expanding conical nitinol frame with an inner waist and six circumferential fixation arms that engage and anchor the valve between the native leaflets and the adjacent walls. It is delivered sful use .via either transapical or transfemoral access via a 35Fr delivery system. It is designed for mitral and tricuspid intervention. It features the ability to perform multidirectional steering and has a unique atrial-to-ventricular deployment. An early feasibility study is continuing recruitment (NCT04433065).Intrepid  is a circular inner stent that houses a trileaflet bovine pericardial valve and is delivered Other TTVR devices are within preclinical and FIM studies. They include TriCares , VDyne , and CardioValve .Caval valve implantation is considered an alternative option as a palliative treatment where direct tricuspid intervention, transcatheter or surgical, is deemed unsafe, unsuitable or is not available. Such scenarios include patients with an enormous tricuspid annulus and large coaptation gap rendering TTVR or leaflet approximation impossible. Likewise some patients with carcinoid heart disease develop TV thickening and dysfunction due to fibrotic plaque deposition at the leaflet tips, making leaflet approximation challenging. Conceptually, caval valve implantation  aims to reduce venous congestion. It can be performed using a dedicated implant  or utilising a balloon-expandable valve with pre-stent implantation for anchoring. Imaging requirements are minimal and the devices may be implanted using fluoroscopic imaging and contrast angiography.TricValve  is a 27.5Fr transfemoral system with two self-expanding caval valves. The SVC valve has a central belly to better prevent dislodgement, a long skirt to reduce paravalvular leak and an uncovered superior segment to allow innominate vein flow. The inferior vena cava (IVC) valve is of higher radial force to support fixation and has a short skirt to avoid hepatic vein obstruction. SVC stenting is performed with a stiff wire from the right femoral vein to either the right subclavian or internal jugular vein. Then valve deployment should start high so that there can be some gentle downward device traction to improve stability and is recapturable to 80% deployed. For IVC deployment, the IVC stent has a short covered section and it’s superior aspect should be near the RA junction. The valve is deployed again starting superior with downward traction to land between the RA and the hepatic vein. Imaging considerations to ensure anatomic suitability include sequential anteroposterior measurements of the SVC (maximum 34 mm) and IVC (maximum 43 mm), length of SVC to middle of perpendicular right PA and SVC-to-RA length and length of IVC from RA junction to hepatic veins (at least 10 mm). SVC stenting can be done in patients with CIED with leads trapped behind the stent. This device avoids TV/RV anatomical exclusions and can be fluoroscopically-guided avoiding general anesthesia. However it does require intraprocedural contrast angiography.The TRICUS EURO study of thirty-five implants showed 94% procedural success with one SVC prosthesis migration without embolization . At six Tricento  is a 24Fr transfemoral system that has a long self-expanding nitinol stent frame designed for the custom length from superior SVC to above the hepatic vein. Within this is a lateral bicuspid pericardial tissue valve that is orientated to be facing the RA on deployment. This single device implant can accommodate pre-screened diameters of 16 to 35 mm for the vena cavae, 40 to 80 mm RA length and at least 10 mm distance from RA to hepatic vein. This system can accommodate existing CIED leads and can be done without general anesthesia but does require contrast angiography.3 to 221 ± 46 mm3 , an interesting finding albeit in a small cohort. Three patients had stent fracture detected without valve compromise and were thought to be associated with massive TR with high mechanical stress during systole applied to the stent segment facing the caudal valve frame.21 patients were analyzed with 100% procedural success at mean total procedure time and device time of 92 ± 48 min and 20 ± 7 min, respectively, . NYHA clCAVI is a somewhat simplified and commercially-feasible option for patients being considered for palliative caval valve implantation. This involves transfemoral balloon-expandable valve implantation  within a self-expanding IVC stent. One study comparing CAVI to medical therapy demonstrated only short-term improvement in dyspnea that did not persist and high incidence of both procedural complications and valve/stent migration culminating in early termination of the trial . This tePost-procedural care in this heterogenous population must be tailored to the patient and the procedure. While there are broad approaches to managing this patient group, it should be patient-specific based on medical history, volume status, type of intervention performed and its success, residual TR and RV function and need for/timing of anticoagulation. Diuresis is generally continued, particularly after non-replacement therapies, with thorough evaluation of how the RV has tolerated the intervention and monitoring of urine output and renal function. Hemodynamic compromise is more common post TTVR where TR is suddenly eliminated and RV afterload is increased. It is not uncommon to continue inotropic support post-procedure and is often required for several days to allow steady volume optimisation and early RV reverse remodelling with support. In contrast, there are patients who tolerate leaflet approximation and are suitable for discharge day one post-procedure assuming no procedural injury.Currently, anticoagulation is recommended post TTVR which should be initiated as early as safely possible, considering bleeding risks related to the patients history, access-site and even TEE-related gastrointestinal bleeding. Anticoagulation is often already indicated in this cohort who often have a separate indication, commonly for atrial fibrillation. All-cause major bleeding is still a common occurrence in this cohort of significant morbidity, at an incidence of 10%–15% across different platforms , 73, 74.The incidence of new pacemakers following surgical TV repair may be as high as 14%  and so cGiven the large unmet need by the previous undertreatment of TR, and the relative safety of TTVI from early studies, the landscape of transcatheter TV interventions is rapidly expanding. In this setting our understanding of the disease pathophysiology and our ability to evaluate, both with non-invasive and invasive tools, has also advanced. These assessment tools may allow for greater standardisation of TV disease definitions , severitTV intervention is still somewhat in its infancy and as utilisation and familiarity increases, questions relating to device selection and durability continue to be studied. Clarity regarding best device with regards to comparative safety and clinical outcomes will continue to improve with more published data and analysis. Even though the older population currently being treated is often of high-morbidity with poor life expectancy, transcatheter interventions should aim to replicate surgical interventions with regards to longevity and freedom from re-intervention. Concomitant transcatheter treatment of TR at the time of non-tricuspid interventions, attempt to mimic surgical management of multi-valvular disease, however the advantage to transcatheter device therapy is the ability to stage these therapies and possibly reduce unnecessary procedures .Device companies continue to innovate based on real and perceived limitations of current devices. Two novel examples are TriFlo (TriFlo Cardiovascular), a novel three-anchor annular device with a central “mini-valve” and the CroiValve DUO , a coaptation spacer valve attached to an SVC stent anchor system that has fewer anatomical contraindications. These devices theoretically can offer treatment to extreme annular anatomies and coaptation gaps, a major limitation across current platforms. TV device therapies will continue to evolve given the anatomical limitations of many of the current therapies prohibiting treatment in many patients.From a procedure perspective, there are some notable drawbacks that are similar to struggles that existed early in aortic and mitral interventions. First, procedural times are long but with familiarity and experience with these techniques and systems, times appear to be improving. However, clearly the anatomy of the TV and related structures is very complex, and currently the reliance on TEE for procedural guidance requires both proceduralist and imaging operator experience and expertise. ICE has an established role in structural intervention and its imaging improvements, with new 4D-capable probes may reduce the imaging intensity as well as imaging-related complications of TTVI. Besides imaging device improvements, device companies will need to continue improving on device safety  and operator usability much like the advancements seen in the transcatheter aortic devices. Further improvements in delivery systems that allow for responsive multiplanar flexion capabilities will assist with anatomical difficulties including IVC-to-tricuspid annulus offset .The lifetime management of patients with valvular heart disease must also be considered, as earlier intervention becomes a reality. Procedural “repeatability” and “durability” will start to play a role in TV interventions as it has in TAVR. TTVR and annuloplasty therapies will theoretically allow for a valve-in-device procedures. Removing TEER devices has become a reality with the recent report of mitral TEER electrosurgical laceration followed by transcatheter mitral valve implantation for persistent mitral regurgitation .Structural heart disease management of TR continues to evolve but without early diagnosis and referral, outcomes may not improve. Education of the primary care physician and primary cardiologist in the identification of the symptomatic TR patient and the appreciation of the adverse outcomes associated with even mild disease,  is imperTTVI is expanding at a rapid pace, allowing for broader eligibility for transcatheter intervention for severe TR. Many of the current TTVI devices appear to have safe, efficacious profiles and can mostly accommodate the various TR etiologies. The current randomized clinical trials should help answer the unknowns related to patient selection, device efficacy and long-term outcomes. As clinical experience continues to grow and newer-generation devices are developed, TTVI appears likely to follow the path of transcatheter aortic and mitral interventions as an accessible and beneficial therapeutic option for this underserved patient population.RH reports speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, and Philips Healthcare; she has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis; she has Equity with NaviGate. The remaining authors have no disclosures to report.DB wrote the initial draft. RH performed extensive editing and content review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A ventriculografia foi utilizada, por anos, como método padrão-ouro para função ventricular. O que este minieditorial relata são algumas considerações que tentam preencher esse vazio.2No que diz a respeito à ventriculografia, podem ocorrer algumas complicações, como a nefropatia induzida por contraste (NIC), que ocorre em, aproximadamente, 1% dos pacientes sem fatores predisponentes e, em 10% a 30% daqueles com fatores de risco, embolização, arritmias e tamponamento cardíaco, e uma maior exposição à radiação.3É necessário que a ventriculografia seja feita com boa qualidade e, para isso, alguns pontos precisam ser elencados, como as injeções realizadas de forma manual, a quantidade de pressão ou até mesmo injeções manuais que podem até ser perigosas se realizadas por meio de cateter com único orifício final. Além disso, os volumes de contrastes devem ser suficientes para opacificar o ventrículo e o posicionamento adequado, permitindo a quantificação automatizada e precisa dos volumes do ventrículo esquerdo e dimensões da aorta.4A fração de ejeção determinada visualmente pela ventriculografia esquerda correlaciona-se de forma variável à fração de ejeção da ecocardiografia. Já em relação à ventriculografia esquerda biplano, esta se correlaciona melhor do que a ventriculografia esquerda monoplano quando comparada à ressonância magnética cardíaca (RM) para fração de ejeção, volumes ventriculares e movimentação da parede.5A decisão de realizar a ventriculografia quando há outros métodos diagnósticos tem sido individualizada, variando também entre regiões geográficas e hospitais.6 Ademais, foram selecionados pacientes com 18 anos ou mais, atendidos em caráter de urgência ou com suspeita de DAC, e que passaram pelo procedimento da angioplastia.No estudo realizado por Lima Santos et al., foram analisados prontuários de 600 pacientes submetidos à cineangiocoronariografia. Destes, 324 fizeram o exame de ventriculografia.No estudo, em relação às variáveis, 89.8% dos pacientes realizaram o exame no período diurno, 33,75% tinham função ventricular conhecida e 283  tinham síndrome coronariana crônica. Outrossim, ao ser avaliado o uso do contraste, observou-se que foram utilizados apenas 3 ml a mais, quando comparado aos pacientes que não utilizaram ventriculografia, o que chamou a atenção, visto que geralmente utiliza-se 30 ml a mais para realização do exame.O paciente com diagnóstico de síndrome coronariana crônica tem, de maneira independente, maior chance de realizar ventriculografia. Por outro lado, ter a função ventricular esquerda conhecida, ser hipertenso, ter sido submetido à revascularização cirúrgica previa e apresentar valores aumentados de creatinina associaram-se com maior chance de não realizar a técnica.Tais dados, até então, eram compatíveis com a literatura, porém, um achado inesperado no estudo sobreveio: a ventriculografia foi mais utilizada em pacientes com síndromes coronarianas crônicas do que naqueles com síndromes coronarianas agudas, o que, na teoria, poderia exigir uma avaliação mais imediata.strain global longitudinal (SGL) das paredes do VE, pelo diagnóstico precoce das alterações isquêmicas em pacientes com alteração de troponina, todavia, sem alteração do ECG ou ecocardiograma de repouso.7Métodos não invasivos, como as novas tecnologias desenvolvidas nos aparelhos de ecocardiografia, têm sido possíveis por meio da análise do 8 sendo importante ressaltar que, nesses casos agudos, a presença de um defeito de enchimento apical sugestivo de trombo não deve ser negligenciada, pois pode ser visualizado na ventriculografia, mas não observado no eco trans torácico sem contraste.9Nos pacientes com choque cardiogênico, a avaliação da função ventricular pode ser prejudicada, pois o miocárdio encontra-se atordoado,10Outra necessidade no infarto com supra de ST seria avaliar complicações como ruptura aguda de parede livre, comunicação interventricular, insuficiência mitral e síndrome de Takotsubo.Na amostra, não houve nenhum paciente com complicação mecânica, portanto, essa situação não foi avaliada no estudo.11No caso de síndrome coronariana sem supra de ST, com eletrocardiograma não interpretável e doença em mais de um vaso, a ventriculografia pode ajudar na identificação da artéria culpada.Cabe mencionar que neste estudo não existe discriminação se é infarto com supra de ST ou infarto sem supra de ST.Por fim, fica visível que o papel da ventriculografia esquerda evoluiu radicalmente ao longo do último meio século, mas recebeu pouca atenção na literatura acadêmica. É importante lembrar que a técnica e a frequência de uso da ventriculografia esquerda variam entre as regiões, instituições e a decisão do operador.Sugerimos, então, que sejam incluídos nas diretrizes critérios para utilização do método. 1The current guidelines address the indications for left heart catheterization associated with coronary angiography, but most of these instructions do not mention ventriculography, as this test is often at the operator’s discretion. For many years, ventriculography was used as the gold standard method for ventricular function. This mini editorial presents some insights to fill this gap.2Some complications may occur concerning ventriculography, such as contrast-induced nephropathy (CIN) in approximately 1% of patients without predisposing factors and in 10% to 30% of those with risk factors, embolization, arrhythmia, cardiac tamponade, and increased radiation exposure.3Ventriculography must be performed with good quality, and, for that, some points of attention need to be considered, such as manual injections, the amount of pressure or even manual injections that can be dangerous if performed using a catheter with a single end hole. Furthermore, contrast volumes must be sufficient to opacify the ventricle and properly position, allowing accurate automated quantification of left ventricular volumes and aortic dimensions.4The ejection fraction visually determined by left ventriculography is variably correlated with the ejection fraction of the echocardiography. Regarding biplane left ventriculography, it correlates better than monoplane left ventriculography compared to cardiac magnetic resonance (CMR) imaging for ejection fraction, ventricular volumes, and wall motion.5The decision to perform ventriculography when there are other diagnostic methods has been individualized, also varying between geographic regions and hospitals.6 Besides, patients aged 18 years or older, treated urgently or with suspected CAD, who underwent angioplasty, were selected.In the study carried out by Lima Santos et al., medical records of 600 patients who underwent coronary angiography were analyzed, of which 324 underwent ventriculography.In the study, regarding the variables, 89.8% of the patients underwent the examination during the day, 33.75% had known ventricular function, and 283 (47.2%) had a chronic coronary syndrome. Furthermore, regarding the use of contrast, it was found that only 3 ml more were used, compared to patients who did not use ventriculography, which drew attention since 30 ml more is usually used to perform the test.Patients diagnosed with chronic coronary syndrome are independently more likely to undergo ventriculography. On the other hand, having known left ventricular function, being hypertensive, having undergone coronary artery bypass grafting, and having increased creatinine levels were associated with greater chances of not having the technique performed.Such data, until then, were consistent with those found in the literature; however, an unexpected finding emerged: ventriculography was mostly used in patients with chronic coronary syndromes than in those with acute coronary syndromes, which, in theory, could require a more immediate assessment.7Non-invasive methods, such as the new technologies developed in echocardiography devices, have been possible through global longitudinal strain (GLS) of the LV walls to diagnose early ischemic abnormalities in patients with abnormal troponin levels, however, without abnormal ECG or resting echocardiogram findings.8 It is important to emphasize that, in these acute cases, the presence of an apical filling defect suggestive of thrombus should not be neglected, as it may be viewed on ventriculography but not on non-contrast transthoracic echo.9In patients with cardiogenic shock, assessment of ventricular function may be impaired, as the myocardium is stunned.10Another requirement in ST-segment elevation infarction would be to assess complications such as acute free wall rupture, ventricular septal defect, mitral regurgitation and Takotsubo syndrome.In the sample, there were no patients with mechanical complications; therefore, this situation was not evaluated in the study.11In the case of non-ST-segment elevation coronary syndrome, with uninterpretable electrocardiogram and disease in more than one vessel, ventriculography can help identify the culprit artery.It is worth noting that there is no discrimination between ST-segment elevation infarction and non-ST-segment elevation infarction in this study.Finally, it is apparent that the role of left ventriculography has evolved dramatically over the past half-century, but it has received little attention in the academic literature. It is important not to forget that the technique and frequency of use of left ventriculography vary between regions, institutions and according to the operator’s decision.We, therefore, suggest that criteria for using the method be included in the guidelines.


Background and Objectives: Chronic atrial stimulation might impair left atrial (LA) function. We aimed to assess the impact of atrial pacing burden on LA volumetric and functional parameters after implantation of a dual-chamber pacemaker. Materials and Methods: The prospective study included 121 subjects with sinus node disease (SND) or atrioventricular block (AVB) that received a dual-chamber pacemaker. After device implantation, the subjects were divided into three groups: (1) SND with a lower rate (LR) set to 60 bpm and rate response enabled; (2) AVB with an LR set to 60 bpm and no rate response; and (3) AVB with an LR set to 40 bpm and no rate response. Subjects were followed at one and three months. Two subsets of patients with high and low atrial pacing burdens accompanied by low ventricular pacing percentage were analyzed. LA function was evaluated with volumetric and strain parameters from transthoracic echocardiography. Results: The high atrial low ventricular pacing group consisted of 38 subjects, and the low atrial low ventricular group consisted of 22 subjects. When looking at the change in volumetric parameters, we observed a tendency for volumes to increase in both groups; however, only minimal LA volume reached statistical significance at three months in the high atrial pacing group. A trend towards the lowering of an active emptying fraction at one month (p = 0.076) became significant at three months (p = 0.043), and was also only observed in the same group. Moreover, a decrease in the tendency to reach statistical significance at three months for reservoir and contractile strain parameters and stiffness index was only observed in the high atrial pacing group. Meanwhile, in the low atrial pacing burden group, all parameters remained significantly unchanged. Conclusions: The burden of right atrial pacing in patients with preserved left ventricular function negatively influences functional and morphologic LA parameters. Moreover, negative effects take place soon after pacemaker implantation and appear to be sustained. Dual-chamber cardiac pacing improves clinical outcomes and quality of life for patients with bradyarrhythmia. Atrioventricular block (AVB) and sinus node dysfunction (SND) are two of the main indications for cardiac pacing ,2. HowevMartens et al. recently presented a study stating that atrial pacing in CRT patients has a negative effect on LA morphology, has a function that leads to a higher risk of AF onset, and worsens HF . HoweverWe aimed to assess the impact of atrial pacing burden on LA volumetric and functional parameters after implantation of a dual-chamber pacemaker.The prospective study was conducted at Lithuanian University of Health Sciences, Department of Cardiology from June 2020 to November 2021. The study in a prospective manner enrolled 121 subjects who received dual-chamber pacemaker implantation because of documented SND or advanced AVB. Subjects underwent standard device implantation procedure with the RA lead primarily positioned into the RA appendage and the RV septal judged by fluoroscopy. The exclusion criteria were history of persistent AF, significant structural heart disease, left ventricular ejection fraction (LVEF) <50%, and inability to comply with the follow-up regime. Subjects after device implantation were divided into three groups: (1) SND with a lower rate (LR) set to 60 bpm and rate response enabled; (2) AVB with a LR set to 60 bpm and no rate response; and (3) AVB with a LR set to 40 bpm and no rate response. Patients were followed up at one- and three-months visits. During enrollment, clinical characteristics  were collected. The study was approved by the National Ethical Committee and written informed consent was obtained from all patients.Conventional two-dimensional transthoracic echocardiography and color TDI were performed the next day after pacemaker implantation. A commercially available ultrasound system  was used. All investigations were performed by experienced echocardiographers.High-quality apical 4-chamber, 2-chamber, 3-chamber, and parasternal views over 4 consecutive cardiac cycles were recorded and stored for further off-line analysis. Sector width was optimized to maintain high frame rate, and LA foreshortening was avoided. All echocardiographic analysis was performed by the same reader blinded to other study-related parameters including atrial and ventricular pacing burden.LA volumes were measured with two-dimensional echocardiographic images by area–length method from apical 4-chamber and 2-chamber views as recommended by the American Society of Echocardiography . EndocarStrain parameters were analyzed using a commercially available software package . An atrial cycle was used as the reference point . To geneMitral inflow pattern was evaluated by E and A ratio. Septal and lateral mitral annular velocities (E′) were obtained by pulsed-wave tissue Doppler imaging and were averaged. LV diastolic filling pressure index was measured by the ratio of transmitral early diastolic velocity to the mitral averaged annulus velocity by pulse TDI (E/e′). The value of >15 signifies elevated LV filling pressure .Subjects were followed up in the same implanting center. At one and three months, follow-up echocardiography was performed. A 12-lead ECG was taken for every patient to precisely assess the underlying rhythm. A pacemaker read-out was done taking note of atrial and ventricular pacing burdens.A cutoff threshold above and below 40% of right atrial and ventricular pacing was chosen. To investigate the right atrial pacing effect on LA functional parameters while minimizing RV pacing effect, we looked at the groups with high and low RA pacing burden that maintained low RV pacing. Grouping into subgroups based on RA and RV pacing burden did not change during the follow-up period.t-test or Mann–Whitney U test as appropriate. Continuous variables in the same group of subjects at the follow-up visits were compared by paired samples with the Student t-test or Wilcoxon test. Categorical variables were compared using the Chi-square test. To assess baseline LA morphometric parameters distribution at baseline between all groups, an ANOVA model was used. Statistical significance was chosen to be p-value < 0.05. Intraobserver variabilities for speckle tracking measurements were tested in 10 randomly selected patients using the identical cine-loops for each view calculating intraclass correlation. Statistical analysis was performed using SPSS Statistics for Macintosh, Version 24.0 . Data are presented as mean ± SD for continuous variables or as percentages for categorical variables, unless otherwise indicated. The Shapiro–Wilk test was used to determine the distribution of the data. Continuous variables were compared using Student’s A total of 121 subjects  men) were enrolled in the study. Intraclass correlation coefficients for intraobserver variability were 0.962, 0.903, and 0.912 for reservoir, conduit, and contractile strains, respectively. The baseline clinical characteristics are summarized in p < 0.001). Pacing burden remained unchanged in each of the subgroups during the study period (p > 0.05). The high RA low RV pacing group consisted of 38 and the low RA low RV pacing consisted of 22 subjects  that became significant at three months (p = 0.043) was also only observed in the same group. Again, a tendency to decrease reaching statistical significance at three months of reservoir and contractile strain parameters and stiffness index was only observed in the high RA pacing group. Meanwhile in the low RA pacing burden group, all parameters remained significantly unchanged.When looking at change of volumetric parameters, we observed a tendency for volumes to increase in both groups , howeverTo our knowledge, this is the first study investigating atrial pacing burden effect in patients with preserved LVEF undergoing dual chamber pacemaker implantation and addressing RV pacing burden. It adds important novel information about atrial pacing effect on LA function after conventional dual chamber pacemaker implantation, which remains the most common mode of pacing. The main findings are the following: (1) higher atrial pacing burden was associated with a negative effect on LA remodeling parameters following dual chamber pacemaker implantation; (2) higher atrial pacing negatively affected systolic and diastolic LA function; and (3) the negative effects of RA pacing appear soon after pacemaker implantation and appear to be sustained.It has been previously demonstrated the RV pacing, besides affecting LV function, can also have detrimental effects on LA function . HoweverLA size is a predictor of the development of new HF. When HF is present, LA enlargement and dysfunction are important predictors of clinical outcomes. Enlargement of the left atrium is also a marker of disease severity and predicts adverse cardiovascular events in heart failure with preserved ejection fraction (HFpEF). In a study that included 89 normal subjects, 38 asymptomatic hypertensive patients, and 183 patients with HFpEF, NYHA class, diastolic blood pressure, age, and LA dimensions were independent predictors of mortality . In our A study by Liang et al. has previously investigated the acute hemodynamic effect of atrial pacing vs. sensing in patients with heart failure with reduced ejection fraction (HFrEF) undergoing CRT implantation. Their study showed that pacing mode is associated with intra-atrial dyssynchrony and might limit LA preload contribution of LV stroke volume . HoweverIt must be noted that previous studies explored pacing effects on LA function and morphology in CRT setting. Though CRT is more physiological than only RV pacing, it is still artificial. What is more, when choosing CRT as a means of treatment, one tries to achieve the highest ventricular pacing percentage possible. In our study we analyzed patients with low ventricular pacing. Furthermore, having as a baseline HFrEF subjects, often accompanied by secondary mitral regurgitation, a higher degree of LA enlargement experience from such studies might not directly translate to subjects with normal LVEF and no significant structural heart disease. What is more, ventricular pacing in our study was not negligible. The ventricular pacing site also plays a part in LA function and affects its remodeling. Apical pacing has been associated with AF, HF, and mortality . It has In the study conducted by Sade et al. looking into AF onset or recurrence in CRT patient population, a higher RA pacing burden predicted AF-recurrence or new-onset AF, respectively . MaintenAnother novel index that has been previously shown to have a relationship to HF development is the LA stiffness index . In the Though our findings are interesting from a pathophysiologic point of view, an equally important clinical practice aspect is important. As with the well-established detrimental effect of right ventricular pacing on LV function and further device programming considerations evident from previous studies, transferring experience to the level of the atria seems logical, as almost no such data are available . RA paciFirstly, we must acknowledge a relatively small sample size in our study. Second, strain analysis has an image quality-dependent modality. However, we report good intraobserver variability. Thirdly, though pacing programming has been strictly maintained regarding lower rate and rate response during study period, other programming parameters  might have been biased by the implanter. Fourth, a relatively short follow-up period does not allow drawing conclusions on arrhythmia occurrence and further LA function development. Fifth, ventricular pacing burden of up to 40% was considered low RV pacing though it was not negligible. Sixth, the right ventricular pacing site can also have an effect on the left atrium, although it has not been considered in our study.The burden of RA pacing in patients with preserved LVEF negatively influences functional and morphologic LA parameters. Moreover, negative effects take place soon after pacemaker implantation and appear to be sustained.


The decline in cardiac contractility due to damage or loss of cardiomyocytes is intensified by changes in the extracellular matrix leading to heart remodeling. An excessive matrix response in the ischemic cardiomyopathy may contribute to the elevated fibrotic compartment and diastolic dysfunction. Fibroproliferation is a defense response aimed at quickly closing the damaged area and maintaining tissue integrity. Balance in this process is of paramount importance, as the reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis leads to impairment of heart function. Under normal conditions, migration of progenitor cells to the lesion site occurs. These cells have the potential to differentiate into myocytes in vitro, but the changed micro-environment in the heart after infarction does not allow such differentiation. Stem cell transplantation affects the extracellular matrix remodeling and thus may facilitate the improvement of left ventricular function. Studies show that mesenchymal stem cell therapy after infarct reduces fibrosis. However, the authors did not specify whether they meant the reduction of scarring as a result of regeneration or changes in the matrix. Research is also necessary to rule out long-term negative effects of post-acute infarct stem cell therapy. Ischemic heart disease is one of the most common causes of death worldwide . Its mosThe objective of the literature review was to determine whether treatment with mesenchymal stem cells after myocardial infarction has a negative, neutral or beneficial effect on diastolic function and regulation of the extracellular matrix.Increased fibrosis was observed in both the infarct zone (IZ) and the non-infarct zone (NIZ). In the infarct zone, successive reparative fibrosis  was observed ,7. In thFibroproliferation is a tissue defense aimed at quickly closing the damaged area and maintaining the integrity of the heart. Balance in this process is of paramount importance. The reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis (as mentioned above) leads to impairment of heart function. The process of excessive fibrosis results from increased collagen synthesis, which outweighs unchanged or reduced degradation ,10,11. FCardiac insult rapidly activates the matrix metalloproteinases (MMPs), leading to ECM fragmentation. These fragments act as bioactive pro-inflammatory matrikines . In the Fibroproliferation in the infarct zone ispresented in In the last stage, 1.5 months and later, fibrosis also develops in the NIZ zone . In the Ultrasonography is a very helpful diagnostic tool. It enables the monitoring of morphological and functional changes of the heart muscle, along with the assessment of the regional systolic and diastolic functions of the left ventricle. Assessment of left ventricular diastolic dysfunction (LVDD), according to the guidelines of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI), is mainly based on six indicators: E-wave, E/A ratio, septal or lateral e′, mean E/e′, left atrial index volume (LAVI) and peak tricuspid velocity (TRpV) ,37. ThesHowever, other means, such as cardiac MRI and cardiac catheterization, can be more accurate in terms of quantitative assessment and accurate diagnosis of diastolic dysfunction and assessment of cardiac fibrosis. The diastolic function is closely related to the heart rate and rhythm, atrial function (mainly systolic), ventricular compliance, preload and atrioventricular valve function. Diastolic dysfunction is therefore a reflection of impaired left ventricular relaxation, resulting from its increased stiffness (advanced stages) and increased filling pressure (even more advanced stages) ,38.The development of regenerative medicine and stem cell treatment of coronary heart disease has become a matter of interest for many scientists. It has been observed that, after myocardial infarction, the number of circulating endothelial progenitors CD34+ and CD133+ KDR and mesenchymal cells increases . It has The key factor affecting the diastolic dysfunction of the myocardium as a result of myocardial infarction and dysregulation of the ECM in the context of MSC therapy is the type of stem cells supplied. Some stem cells seem to have greater differentiation capacity, while other may have greater paracrine activity or greater potential to stimulate neovascularization. It was reported that MSCs obtained from the subcutaneous white fat tissue of the abdomen of a pig , injected into a pre-planned area, improved left ventricular systolic function and reduced the scope of the infarction . It alsoMany studies indicate a low immunogenicity of MSCs, thanks to which a single transplant is well tolerated by the recipient organism. However, repeated administration of MSCs may result in the production of all antibodies. Von Bonin et al., reported that the transplant of MSCs, which had contact with fetal bovine serum (FBS), induced the production of antibodies against FBS in the blood of the recipient. It is worth emphasizing that FBS is often used in the MSC culture medium. Thus, MSCs are dualistic in nature.Research shows that, thanks to the use of the latest pharmacological treatment methods on people with MI, we are able to eliminate clinical symptoms, but we are not able to eliminate fibrosis ,47. The Despite significant progress in this method of treatment, cell transplants still have an insufficient degree of implantation in the damaged heart and insufficient survival in the area of damage. In the years 2010–2020 several randomized and multicenter studies of the treatment of ischemic heart disease were carried out, using mainly autologous bone marrow-derived mononuclear cells, but also selected bone marrow cells. All these studies showed no additional benefit over standard therapy ,63,64,65An adult heart muscle has more fibroblasts compared to resident heart progenitor cells . Therefore, the concept was developed to increase the endogenous regenerative potential of an adult heart, performed by reprogramming fibroblasts with the use of retroviruses into ESC-like cells  and then into new cardiomyocytes . Using gExcessive cardiac fibrosis, associated with diastolic dysfunction, is still a clinical problem. There has been no uniform approach to remodeling therapy for several decades. Preventing post-infarction ECM remodeling seems to be very important, because it prevents such dangerous consequences as left ventricular dilatation and rupture ,6,15,73.In conclusion, cellular therapy for heart regeneration has much room for improvement before being considered an affordable, widely available, safe and effective clinical approach. It seems that studies should be carried out at this stage on animal models, as the effects of both non-hematopoietic and hematopoietic stem cells may differ in vitro and in vivo. Long-term research performed to rule out long-term negative effects of post-acute MI stem cell therapy, including diastolic failure, will also be necessary.


The aim of this study was to investigate the changes of syndecan-4 (SDC-4) during the hypertensive period in two kidney-two clip (2K2C) hypertension rats and compare them to brain natriuretic peptide (BNP) and the echocardiographic parameters for diastolic function evaluation in the rat model of 2K2C hypertension. n = 21) and the sham-operated group (n = 15) were equally divided into 3 subgroups according to the schedules . Serum SDC-4 and BNP were detected by ELISA, and echocardiography indexes were acquired.  A total of 36 Sprague–Dawley (SD) rats were used in this study. Hypertension was induced in 21 by 2K2C surgery, and 15 were sham-operated. Both the 2K2C hypertension group .  The level of SDC-4 and cardiac fibrosis increased gradually as the experiment was processed, and BNP, Tei index, and E/E′ followed to be raised as high blood pressure was maintained after four weeks in the 2K2C hypertension rats. In the earlier 4 weeks, only SDC-4 and cardiac fibrosis were significantly increased in 2K2C hypertensive rats in comparison with normotensive rats. And it was shown that SDC-4 was positively correlated with BNP level during the entire study ( SDC-4 increases gradually during the process of diastolic dysfunction in 2K2C hypertensive rats. SDC-4 is the earliest biomarker reflecting diastolic dysfunction in this model, superior to E/E′ and the Tei index. Our results indicate that serum SDC-4 could act as an early biomarker to show diastolic dysfunction. Hypertension is a major cause of heart failure by the initiation of left ventricular hypertrophy and coronary atherosclerosis. Left ventricular hypertrophy is not only the result of cardiac myocyte hypertrophy but also of increased extracellular matrix and collagen structure , 2. Bothβ after pressure overload [Previous studies have shown that left ventricular transmembrane proteoglycan syndecan-4 (SDC-4) is increased in mice and humans through inflammatory mediators such as TNF-a and IL-1overload , 7. And overload .Echocardiography can detect the cardiac structure and function of patients with hypertension as well as provide prognostic information. Echocardiography is a preferred method for differentiation of normal ejection with impaired diastolic function.SDC-4 was described as essential to developing heart failure in response to pressure overload . But fewn = 21) and the sham-operated group . Both the 2K2C and Sham groups were equally further divided into 3 subgroups (7 per subgroup for 2K2C and 5 for Sham). Blood pressure, weight, echocardiographic scans, myocardial fibrosis, as well as SDC-4, and BNP were recorded on 4th, 8th, and 12th week after the operation.A total of 36 healthy Sprague–Dawley (SD) male rats  were used in the study. The rats were housed in groups of five a cage with free access to food and water, kept in consistent condition, in a temperature-controlled environment (20–25°C) with a 12 h light/dark cycle. The rats were randomly divided into 2 groups: the 2K2C hypertension group  and approved by the Institutional Animal Care and Use Committee and the Ethics Committee of the First Affiliated Hospital at Sun Yat-sen University.The two kidney-two clip (2K2C) hypertension rat model was prepared as follows: Under anesthesia with 3% sodium pentobarbital (36 mg/kg body weight IP), a median longitudinal incision on abdominal skin was made, then both the right and left renal arteries were constricted by placing ring-shaped silver clips with an inner diameter of 0.30 mm to induce hypertension. The ring of the clip was placed around the renal artery, and then the outer gap of the clip was shut. Abdominal contents were undamaged and were carefully returned to the original location. The abdominal wall and skin were sutured. The sham-operated group also underwent the same surgical procedure but without a vascular clip .The SBP of every unanesthetized rat was taken in each group at 4 w, 8 w, and 12 w postoperation using the tail-cuff method. The SBP was taken three times; the average reading was recorded. Before taking the blood pressure, the rats were warmed up at 35°C in a cage for 10 minutes. This procedure was required in order to obtain constant and stable blood pressure.The cardiac function was evaluated by serial transthoracic echocardiography at 4 w, 8 w, and 12 w postoperation. Echocardiographic studies were performed with an 11.5-MHz transducer using a GE Vivid i digital ultrasound system . All scans were averaged over 3 cardiac cycles. The images were stored in DICOM format for further analysis.A 2D guided M-mode echocardiography was obtained from the parasternal short-axis view at the papillary muscle level. The measurements of the end-diastolic ventricular septum (IVSd), end-diastolic and end-systolic left ventricular inner diameter , and end-diastolic left ventricular posterior wall thickness (LVPWd) were measured in this image. Then, the ejection fraction (EF) and shortening fraction (FS) were calculated by the Teich method. LA anteroposterior diameter (LAd) was measured in the parasternal long-axis view using M-mode echocardiography.The Devereux's formula used to estimate left ventricular mass index (LVMI) was as follows:K is 9.1 for rats, and W is the body weight (g).The skin surface areas (BSA) of the rats were measured using the Meeh–Rubner  equationE) was measured. Tissue Doppler imaging was performed to detect E′ velocity by the same sample volume and speed at the septal and lateral mitral annulus. The ratio of E to E′ (E/E′) was calculated.Mitral inflow was assessed from the apical 4-chamber view with pulsed-wave Doppler by placing a 0.5 mm sample volume between the tips of the mitral leaflets during diastole at a speed of 200 mm/s. From the mitral inflow profile, peak early diastolic left ventricular filling velocity  and left ventricular ejection time . Tei index was calculated as follows:  (4)MCOT−The collected samples of blood were placed in two serum separator tubes to clot for two hours at room temperature, and then they were centrifuged for 20 minutes at approximately 1000 rpm. Next, the samples were kept at −80°C until the time for tests. The titers of syndecan-4 and BNP were determined by the Sandwich Enzyme-Linked Immunosorbent Assay (ELISA), and the ELISA kits were supplied by Cloud-clone Company .Hearts were excised for histological analysis at predetermined time points. Heart samples were fixed by perfusion with 10% formaldehyde and excised immediately. Next, hematoxylin-eosin staining and Masson's trichrome staining were performed. The expression of fibrosis was quantified by computer graphic software  .n = 7 for 2K2C for each time point) and compared with age-matched control groups (n = 5 for Sham for each time point). All variables were expressed as the mean ± standard deviation. The student's independent t-test was used for intergroup comparisons (two groups), including SBP, echocardiographic parameters , serum BNP, and serum SDC-4. Differences between the two groups (2K2C and Sham) were considered statistically significant if P < 0.05. Pearson's linear correlation analysis was used to determine the correlations between serum levels of SDC-4 and BNP, CVF, E/E′, and Tei index.SPSS Statistics 19.0  was used for statistical analysis. The data were assessed at 4 w, 8 w, and 12 w postoperatively     as shown in E/E′ ratio, BNP, and Tei index in Pearson's analysis , as well as with fibrosis area (CVF)   . These dE/E′ were continuously increasing, which were correlated to left ventricular diastolic dysfunction.In this study, it was found that the expression of SDC-4 was closely related to the diastolic dysfunction in the two kidney-two clip (2K2C) hypertensive rat model. As high blood pressure was maintained after four weeks in the 2K2C hypertension rats, the levels of SDC-4, cardiac fibrosis, brain natriuretic peptide (BNP), Tei index, and E/E′ ratio can be used to predict LV filling pressure, and it is an important and recommended variable for identifying left ventricular diastolic dysfunction in hypertensive patients [Hypertension leads to left ventricular hypertrophy by increasing stress on the cardiac wall. But, left ventricular hypertrophy is hardly seen in early and mild hypertension; usually, diastolic dysfunction is the first sign of hypertension . Echocarpatients .E′ in bilateral mitral valve annulus, increased Tei index, and E/E′) had significantly changed in the hypertensive rats compared to the sham group. It was shown in this study that the left ventricular diastolic dysfunction had emerged without left atrial enlargement in the 2K2C hypertensive rats after 4 weeks continuously under high pressure.In this study, it was found that the left atrium of hypertensive rats without treatment for 4 weeks did not enlarge, while left ventricular wall thickness and left ventricular mass obviously increased. Meanwhile, Doppler variables .Testing of natriuretic peptides is useful in the evaluation of patients who are suspected of having heart failure with preserved ejection fraction. When the BNP is 35 pg/ml or higher, TTE should be recommended to evaluate the left ventricle systolic and diastolic function in patients . The proThe Tei index, a Doppler parameter, is defined as the sum of the isovolumic contraction and relaxation times divided by the ejection time. It can be used to access the global left ventricular function . And, thE/E′, and larger atrial), which indicated that pressure-overload elevation might contribute to the normal Tei index.In this study, compared to the normotensive rats, the Tei index increased gradually after four weeks in 2K2C hypertensive rats. This phenomenon is seen in most studies , 21. ButPrevious studies showed that SDC-4 played an important role in compensating for hypertrophy and maintaining cardiac function during the process of heart failure due to pressure overload . SDC-4 iPressure overload, i.e., hypertension, leads to ventricular stiffness, which may cause diastolic dysfunction. Cardiac fibroblasts play an important role in myocardial stiffness. Collagen cross-linking is one of the factors that explains the overexpressed myocardial stiffness –27. The st week in transverse aortic constriction pressure-overloaded mice [E/E′, and Tei index.It is demonstrated that SDC-4 promotes myofibroblast differentiation and collagen production upon mechanical stress by the action of the nuclear factor of activated T-cells (NFAT) , 7. Simided mice , 23. TheInterestingly, our study found that, in the early 4 weeks, only SDC-4 showed significant elevation in 2K2C hypertensive rats, while cardiac fibrosis increased at the same time. It demonstrated that SDC-4 was closely related to cardiac fibrosis in the overpressure-loaded model. In addition, SDC-4 might act as an early biomarker for identifying heart failure, especially in the left ventricular diastolic dysfunction in 2K2C hypertensive rats.E/E′, and Tei index.This article is not intended to discuss the clinical situation because the hypertensive model is unable to represent the clinical status. The pathogenesis is explored in this study partially because other studies have reported some theories to explain why the expression of syndecan-4 is related to diastolic dysfunction. This study focuses on the correlation between the expression of syndecan-4 and diastolic dysfunction in hypertensive 2K2C rats, and further experimental studies are required to investigate the therapeutic effects on the changes of syndecan-4, The present study indicates that SDC-4 is an early biomarker that changes significantly in comparison with other data, as SDC-4 level increases gradually during the process of diastolic dysfunction in two kidney-two clip hypertensive rats. It could be implied that SDC-4 might be used as an earlier biomarker to indicate early diastolic dysfunction than echocardiography.


Comparison to classification based on in vivo rotational NOGA XP maps showed no correlation. Thus, isolated changes of the electromechanical activation sequence in the left ventricle are not sufficient to reproduce the rotation pattern changes observed in vivo and suggest that further patho-mechanisms are involved.Cardiac resynchronization therapy is a valuable tool to restore left ventricular function in patients experiencing dyssynchronous ventricular activation. However, the non-responder rate is still as high as 40%. Recent studies suggest that left ventricular torsion or specifically the lack thereof might be a good predictor for the response of cardiac resynchronization therapy. Since left ventricular torsion is governed by the muscle fiber orientation and the heterogeneous electromechanical activation of the myocardium, understanding the relation between these components and the ability to measure them is vital. To analyze if locally altered electromechanical activation in heart failure patients affects left ventricular torsion, we conducted a simulation study on 27 personalized left ventricular models. Electroanatomical maps and late gadolinium enhanced magnetic resonance imaging data informed our in-silico model cohort. The angle of rotation was evaluated in every material point of the model and averaged values were used to classify the rotation as clockwise or counterclockwise in each segment and sector of the left ventricle. 88% of the patient models ( In the healthy human heart, left ventricular (LV) ejection and filling is supported by the twisting and untwisting of the ventricle during systole and diastole, respectively. This twisting or wringing motion is determined by several anatomical and physiological features such as age, contractility, structure of the myocardium, and muscle fiber orientation . FurtherIn pathological cases, this wringing motion of the LV can be disrupted by dyssynchronous mechancial activation resulting in a reduced LV ejection fraction (EF) . Dyssyncin vivo electromechanical mapping data. Specifically, we hypothesized that the altered electrical activation pattern is sufficient to change wringing rotation to RBT. Spatiotemporal electromechanical parameters including local activation time (LAT), local rotational electromechanical delay (LEMD), and total rotational electro-mechanical delay (TEMD) were combined with local scar burden derived from late-gadolinium-enhanced cardiac magnetic resonance imaging (LGE-MRI) and incorporated into the LV model. LV rotational patterns are analyzed and classified into two groups defined as normal wringing rotation and RBT. Finally, the classification based on the simulation results is compared to the clinical classification.As a representation of the LV, we used a truncated ellipsoid with varying wall thickness. The wall thickness changes from 7 mm at the base to 3.5 mm at the apex. With a sphericity index of 1.58, the ellipsoid has a similar shape as the left ventricles of the patient cohort in Q = {f0, s0, n0} of the myocardium with fiber angles of 60°at the endocardium and -60°at the epicardium  as the Jacobian, and ρ0 as the density in the reference configuration. Furthermore, we introduce the right Cauchy-Green tensor C = FTF. The second Piola-Kirchhoff stress tensor S = S  incorporates both, the passive and active mechanics of the myocardium using the relationshipκ, shear modulus μ, and dimensionless orthotropic scaling factors bij, i, j ∈ f, s, n. Active stress due to the contraction of the cardiac muscle acts along the myocyte orientation f0 with the scalar value of the contractile force Ta = Ta . The simplified model by λf is the fiber stretch, and ta is the time of mechanical activation determined from electroanatomical mapping as detailed in pLV(t) applied by the blood inside the LV. pLV(t) is determined by a 0D circulation model t ∈ . Additionally, the interaction between the LV epicardium pLV = 8 mmHg by solving the static problemu. Finally, this displacement is used as an initial condition u0 for the problem described in The kinematics of the LV are determined by solving the governing equation for the balance of linear momentum:g tissue  is consiThe mathematical model described here is a reduction of the four-chamber model presented in n = 21). Mean left ventricular ejection fraction, end-diastolic volume, and end-systolic volume were 30 ± 6%, 240.5 ± 65.8 ml and 178.4 ± 49.4 ml, respectively. All individuals presented sinus rhythm and LBBB morphology on 12-lead ECG with a mean QRS duration of 168 ± 17 ms. For the enrollment of patients, the LBBB criteria of ta = LAT + LEMD in each segment and assigned to the center of the endocardial surface that belongs to the corresponding segment. To avoid sharp transitions between the segments due to the low resolution of the available LEMD data, all values are interpolated over the whole endocardium using Laplacian minimization (X based on the distance from the endocardium D(X):The measurements from each patient were incorporated into the LV geometry presented in mization . The res0.4 m/s . This adTpeak was reduced by the same amount as the percentage of the measured LGE intensity in the respective segment.Local scar burden was incorporated by the percentage of enhanced area determined from LGE-MRI measurements on a segment-by-segment basis. It is assumed that the myocardium in enhanced areas was subject to remodeling processes and thus shows a decreased contractility. To reflect this in our model, the maximal contractility z-axis of the global coordinate system in basal-apical direction. Hence, we extract all endocardial points x, y) plane, and use the relationshipα from end-diastole (ED) to end-systole (ES). The direction of rotation was determined throughpLV(VLV) resulting from the 0D circulation model The main focus of this study is to determine different rotation patterns in the LV emerging from locally altered electromechanical delay. Therefore, we need to calculate the rotation angle as well as rotation direction of points located on the endocardial wall with respect to the heart’s long axis. Notice that only endocardial points are evaluated since the clinical data was measured with an intracardiac mapping device. In our idealized LV model, the long axis corresponds to the We studied how locally altered electromechanical activation determines the diverse LV rotation patterns observed in HFrEF patients diagnosed with LBBB using in-silico models of the LV in a total of 31 cases. 30 of them were informed by patient specific measurements of LAT and LEMD using the measured data reported in Based on The results for the Control case are shown at the top. In the first 100 ms, the LV experienced a short untwist meaning that apical segments rotated clockwise with up to −3° and basal segments rotated counterclockwise with up to 1°. Right after this first phase, apical and basal segments start to rotate in the opposite direction until end-systole is reached (at about 410 ms). The mean angle of rotation was 18°, 5°, and −6° for the apical, medial, and basal sectors, respectively. At the bottom of Compared to the Control case, Case 18 showed a markedly different contraction pattern . Most noTwo examples of the difference in the evaluated angle of rotation are given in n = 6) and 80% in Group B (n = 24). Furthermore, 73% (n = 22) of patients in Group B showed clockwise RBT rotation and predominantly counterlockwise RBT rotation was observed in 7% (n = 2). Compared to the clinical classification, the in silico model results yielded matching classifications for Group A in 50% (n = 3) of the cases and in 0% of the cases for Group B.Lastly, the results of the binary classification for each of the 17 AHA segments in the Control case and the 27 clinically informed simulations are shown in We presented results of a total of 27 mechanical simulations of an idealized LV that were informed by electroanatomical maps recorded with the NOGA XP system and additional LGE-MRI data. Results of one additional simulation without a patient specific input served as a control case. We evaluated the angle of rotation of each point on the endocardium and accumulated mean values on a segmental (17 AHA segments) and sectorial  basis. Based on the segmental mean values, we determined the direction of rotation to be either clockwise  or counterclockwise . Finally, each simulation was classified as wringing type rotation (Group A) or RBT rotation (Group B) and compared to the clinically assessed classification.The Control case was parameterized to yield a physiological contraction pattern that could be used as a comparison since all other cases involve data from patients suffering from HFrEF and LBBB. Hence, we presumed the electrical activation to be synchronized such that the subendocardial mechanical contraction is homogeneous throughout the LV and spreading transmurally towards the epicardium. The evaluated rotation pattern concurs with observations made in healthy individuals quantitatively and qualitatively . First, Electrical activation and consequently mechanical contraction of the LV in the pathological cases was determined by patient specific measurements of electroanatomical maps. LAT and LEMD were directly integrated into the LV model using the segments defined by the NOGA XP catheter system. LGE-MRI intensity was used as a surrogate for scar tissue in the LV. Typically, scar tissue undergoes a remodeling process that involves build-up of collagen in the myocardium , which cThe classification into Group A (wringing rotation) and Group B (RBT rotation) was based on the evaluation of the mean angle of rotation in the 17 AHA segments. It clearly showed that most cases were classified into Group A. With the exception of 3 cases, all cases were classified different than in the classification based directly on the clinical rotation data, which means we cannot confirm the hypothesis postulated in 1. LEMD was defined as the time interval between the local electrical activation of the segment and its peak systolic rotation, not the onset of mechanical activation. If we assume a similar length of active contraction in each segment, this should not pose a problem and LEMD can be interpreted as a local delay. However, different contractility can be expected especially in segments that show enhanced regions in LGE-MRI due to scar tissue and the associated tissue remodeling. This is especially important, since we observe a significantly longer time interval between electrical activation and peak systolic rotation in our simulations .2. The presented in silico model neglects the influence of the atria and the right ventricle on rotation of the LV. Atrial data was not available for these patients at all and for the right ventricle no electroanatomical mapping data was available. Therefore, we decided to use the same LV geometrical model for all patients to isolate the effect of electromechanical activation on rotation. Especially the absence of the right ventricle might be crucial to why we can not observe clear rigid body rotation in the in silico model. The patients in the clinical cohort all presented with LBBB, meaning that the right ventricle contracted first. This might result in a lateral displacement of the septum. Consequently, an initial fraction of the active force generated by the LV contraction is spent on reversing this displacement instead of storing the entire energy in torque which ultimately results in less rotation. In our model this is not considered, which is why we might not be able to observe rigid body rotation.3. A reason for the small differences in simulations in which scar burden was considered could be the simple way of transferring LGE intensity directly into a decrease in contractility. Although it is a straightforward approach and easy to implement, scar tissue is more complex and typically accompanied by other pathomechanisms in addition to a reduction in contractility. For example, fiber orientation in the LV of patients with dilated cardiomyopathy is typically reorganized Furthermore, the following limitations apply to our study:in vivo data of 30 patients to analyze rotational dynamics in the LV. The main aim of this study was to investigate the specific hypothesis that dyssynchrony alone affects the kinetics of the LV in patients with HFrEF and LBBB in a way that rotational behavior is qualitatively changed. If this was the case, we would have been able to reproduce the mechanical behavior observed in the NOGA XP cardiac mapping system in vivo. The fact that this hypothesis was falsified shows that it is not the electromechanical activation sequence alone that determines rotational behavior suggesting that additional mechanisms are involved. Implications are that further research is required to fully understand the determinants of rotational behavior and that these further (and currently unknown) mechanisms are likely also important to be addressed therapeutically.In conclusion, we combined a state-of-the-art model of heart mechanics and