We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort  with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE, heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell’s C statistics. During follow-up, there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest to 0.715 comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small. Assessment of global left ventricular (LV) systolic function is key to evaluating prognosis and in determining therapeutic strategies in cardiovascular disease (CVD) . ReducedLV strain by 2-dimensional (2D) speckle-tracking echocardiography (STE), particularly global longitudinal strain (GLS), may be superior to EF for prognosis in patients with a range of cardiac disease,  and its Accordingly, we investigated whether multidirectional strain components assessed by 3D-STE predicted major adverse cardiac endpoints (MACE) in a multi-ethnic UK community-based sample. We also evaluated whether 3D-strains were superior to 3D-EF and the additional prognostic utility of 3D-STE over and above established CVDRF and 2D-EF.Fig 1. 3D-STE LV analysis was acceptable in 529 participants (i.e. only 53% of the 1001 participants undergoing 3DE); more details on the feasibility of 3D-STE in SABRE have been reported elsewhere [The design of Southall and Brent revisited (SABRE) study has been described previously ,13. Brielsewhere .The study was approved by St Mary’s Hospital Research Ethics Committee (07/H0712/109) and was performed in accordance with the principles of the Helsinki Declaration. Written informed consent was obtained, including consent for primary care medical record review and data linkage.Echocardiography was performed by two experienced sonographers using a commercially available system (Phillips iE33 equipped with a S5-1 phased array and a X3-1 matrix array transducers). Full detail of SABRE standardized echocardiography imaging, quality control and analysis protocol has been described previously .Chamber dimensions and wall thickness from 2D-guided M-mode were measured from parasternal long-axis view from which LV mass was calculated following ASE recommendations . LV voluImage settings were optimized and 3D LV full-volume dataset of 4 sub-volumes (wide-angled 93°×80°) was obtained from the apical position acquired over 4 cardiac cycles. The presence of an acceptable ECG signal was checked before accepting the loop. Scans were stored on a secure fileserver in DICOM or native format.Fig 2) described in detail elsewhere [3D-STE LV myocardial deformation analysis was performed offline using TomTec 4D LV-Analysis  according to a pre-specified protocol, , and peak averaged segmental LS, CS, RS and 3D-PTS, twist and torsion. 3D-PTS represents the major direction and magnitude of deformation in which no shear strain occurs; it provides an integrated measure of LV 3D deformation that is related to the geometry and active stress generation by cardiac myofibres . Global Participants were followed up until April 2021 or the time of the event for morbidity and mortality by the Hospital Episode Statistics (HES) and UK Office of National Statistics (ONS). Causes of deaths were defined according to the International Classification of Disease (ICD) diagnostic codes (ICD-9 or ICD-10). HES provided information regarding admissions, discharge, and the ICD diagnostic codes and operation codes (i.e. the Office of Population Censuses and Surveys (OPCS) classification of interventions and procedures).The primary outcome was a MACE comprising new onset fatal and non-fatal coronary heart disease (CHD); this was defined as angina, MI or its complications and atherosclerotic heart disease , or emergent coronary revascularization interventions ), HF hospitalization , new-onset AF , ventricular fibrillation , and cardiovascular mortality . CHD events that occurred before SABRE clinic attendance were identified from self-report and primary-care medical record review. Medical record review was undertaken by trained research team members in local general practices and at primary care trusts. CHD events identified from primary care record review were adjudicated by two senior physicians according to the ASCOT study criteria .t-test or a Mann-Whitney test for continuous variables as appropriate and a χ2 test for categorical variables. Analyses were performed using Stata .Continuous variables describing the sample are presented as mean±SD or median (interquartile range) as appropriate. Categorical variables are presented as counts (percentages). Differences between two groups were compared using a two-sample Cumulative hazard curves were created using the Nelson-Aalen method and the median was used to dichotomize continuous predictive variables and statistical testing was performed using a log-rank test. For follow-up time, individuals were censored at the end of the follow-up (April 2021) or at the time of event of interest.a priori based on components of the Framingham risk score (FRS) plus cystatin C as a measure of renal function, but variables with no impact on associations were removed from the final models to preserve model stability relative to number of events , body mass index, smoking, cystatin-C, LV-3DE image-quality score; model-3: model-2 plus prior history of CHD); model-4: model-2 plus 2D-EF). Non-cardiovascular death was considered a competing risk, and therefore competing risk analysis using Fine‐Gray estimators was performed and results presented as a sensitivity analysis.Multivariable associations between 3D-STE-derived LV myocardial deformation/strain indices and outcomes were determined using Cox proportional hazard models, and HR) were reported. Cox regression model diagnostics were performed to check that assumptions of proportional hazards were satisfied. Unadjusted and multivariable-adjusted HR were calculated. Covariates in multivariable Cox regression models were selected While heart rate (HtR) is not routinely included in most risk scores, since HtR is plausibly associated with some of the exposures and the outcome, a sensitivity analysis was performed by adding HtR to model-3. The possibility that prior history of CHD modified associations was investigated by testing for a statistical interaction and a further sensitivity analysis was performed by excluding individuals with prior history of CHD. Key exposures were standardized to facilitate comparisons between HR.2 values), and AIC and BIC were calculated as measures that combine fit and complexity [P-value of <0.05 was considered statistically significant.Harrell’s C statistics obtained from Cox proportional hazards models were used to assess the discrimination of 3D-STE derived LV myocardial strain indices for predicting the outcome to indicate which of the strain components might identify individuals at higher risk. The added incremental value of 3D-EF, 3D-GLS and 3D-PTS in improving cardiovascular risk stratification by FRS was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models for goodness-of-fit , there were 92 MACE (incidence rate = 0.0163 person-yea). The majority of participants had “normal” LV systolic function (3D-EF>50%). Participants with MACE tended to be older, more likely to be men, South Asian, obese, have hypertension, DM, and a history of CHD. In individuals experiencing MACE, LV systolic function, (determined by 2D-EF or 3D-EF) was more impaired, and cavity volumes and LV mass were larger. 3D-GLS, 3D-PTS and 3D-RS were more impaired in participants with MACE compared to those without. Participants in whom 3D-STE could not be obtained were older, more likely to be South Asian, heavier, and to have hypertension, DM, and history of CHD (S1 Table in S1 File).The age of the study sample was 69±6y and 405 (76.6%) were male .Nelson-Aalen cumulative hazard curves for 3D-STE LV myocardial strains and 3D-EF vs. MACE are shown in Table 2 and Fig 3). Evidence of an association between 3D-GCS and MACE was doubtful and evidence for 3D twist and torsion was unconvincing. Associations for 3D-GLS, 3D-PTS, 3D-RS and 3D-EF were little altered following adjustment for CVDRF and LV-3DE image-quality score (model-2). Further adjustment for prior history of CHD slightly attenuated the associations (model-3: Table 2). After inclusion of 2D-EF in models (model-3: Table 2) all associations between 3D-STE LV functional indices were attenuated to the null.In unadjusted Cox analyses, 3D-EF, 3D-GLS, 3D-PTS and 3D-RS were associated with MACE (Table 2); however, differences in C-statistic between all 3D-STE derived strain indices and 3D-EF were negligible.In unadjusted models, 3D-PTS, 3D-GLS and 3D-RS were very slightly stronger discriminators of MACE than 3D-EF (S3 Table in S1 File) and accounting for non-cardiovascular deaths as a competing risk had little effect on estimates (S4 Table in S1 File). There was no evidence that prior history of CHD modified the associations between the outcome, and 3D-STE derived indices. However, associations with the outcome were attenuated after excluding individuals with prior history of CHD, such that there was no convincing evidence of associations with MACE (Table 3), although due to the reduced number of events 95% CI were wide and clinically important associations could not be excluded.Results were similar in models additionally adjusted for HtR (Table 4). Inclusion of both 3D-GLS and 3D-PTS slightly improved the discrimination and calibration compared with 3D-EF (Table 4) but differences between all models, including the FRS model alone, were small. There was no convincing evidence that adding any of these measures improved continuous NRI or IDI (Table 4), although the 95% CI were wide, and it was not possible to exclude clinically important effects.Inclusion 3D-EF, 3D-GLS and 3D-PTS increased the goodness of fit of the model when compared with FRS, but the improvement was modest (Table 4).In a sensitivity analysis, there was no evidence of incremental predictive value of 3D-EF, 3D-GLS and 3D-PTS over FRS for the prediction of MACE after exclusion of individuals with prior history of CHD  is a novel measure which reflects contributions from multiple directional deformations simultaneously, potentially decreasing tracking errors because of higher signal to noise ratio and providing a better assessment of the overall magnitude of deformation ,25. A feA strength of the present study is its prospective, community-based design and the inclusion of a multi-ethnic sample of older men and women with long-term median follow-up of more than a decade. A limitation of this study is the relatively small number of events and the consequent limited statistical power. The use of a composite endpoint may obscure associations for infrequent but important outcomes e.g. HF. The large proportion of people who did not have acceptable 3D-STE is another limitation. Not counting people who attended clinic before the 3D probe was available, acceptable 3D-STE was achieved in only 38% of participants. 47% of participants who had acceptable 3DE did not have acceptable 3D-STE because of a variety of problems, including inadequate frame rate, major stitch artifact, poor ECG signals or inadequate image quality . 3D-STE In a multi-ethnic sample of older people, selected 3D-STE indices of LV myocardial mechanics predicted MACE independently of clinical cardiovascular risk factors but not 2D-EF. 3D-GLS and 3D-PTS were marginally superior to 3D-EF in predicting MACE, but with no convincing evidence of improved reclassification/discrimination. LV myocardial strains measured by 3D-STE adds little prognostic information in elderly community-dwelling individuals.S1 File(DOCX)Click here for additional data file.


Coordinated and harmonic (synchronous) ventricular electrical activation isessential for better left ventricular systolic function. Intraventricularconduction abnormalities, such as left bundle branch block due to artificialcardiac pacing, lead to electromechanical “dyssynchronopathy” with deleteriousstructural and clinical consequences. The aim of this review was to describe andimprove the understanding of all the processes connecting the several mechanismsinvolved in the development of artificially induced ventricular dyssynchrony bycardiac pacing, most known as pacing-induced cardiomyopathy (PiCM). The chroniceffect of abnormal impulse conduction and nonphysiological ectopic activation byartificial cardiac pacing is suspected to affect metabolism and myocardialperfusion, triggering regional differences in the activation/contractionprocesses that cause electrical and structural remodeling due to damage,inflammation, and fibrosis of the cardiac tissue. The effect of artificialcardiac pacing on ventricular function and structure can be multifactorial, andbiological factors underlying PiCM could affect the time and probability ofdeveloping the condition. PiCM has not been included in the traditionalclassification of cardiomyopathies, which can hinder detection. This articlereviews the available evidence for pacing-induced cardiovascular disease, thecurrent understanding of its pathophysiology, and reinforces the adverse effectsof right ventricular pacing, especially right ventricular pacing burden(commonly measured in percentage) and its repercussion on ventricularcontraction (reflected by the impact on left ventricular systolic function).These effects might be the main defining criteria and determining mechanisms ofthe pathophysiology and the clinical repercussion seen on patients. According to Kaye etal.16][.Definition 3: a reduction in LVEF ≥ 10% irrespective ofbaseline LVEF. This definition is relevant as it has been used in previouspublications17][.14][. This cutoff point wasrecently reviewed in the current European Society of CardiologyGuidelines31][ attributed to the “inflammatory” (andtoxic?) process triggered by ectopic electrical activation of themyocyte34][.“Conventional” RV pacing  causes myocardial activation almost in reverse tothat which occurs in intrinsic physiological antegrade conduction using theHis-Purkinje system. It causes delayed and abnormal ventricular myocardialactivation  associated with nonphysiological ventricularcontraction vs. 632 with single-chamberventricular rate-modulated (VVIR) pacing29][. RV PiCM is usually defined as LV systolic dysfunctionresulting from electrical and mechanical dyssynchrony caused by RV pacing. RV PiCMis common and occurs in 10-20% of patients exposed to frequent RVpacing46][.Although the follow-up period in the previous cohort was the longest49][. Paced QRS duration ≥ 163 ms was the mostimportant predictor of HF admission17]. ynchrony[61].62][.A systematic review aiming to compile available data included randomized andobservational studies comparing HBP or CRT 67]) and another using RV pacing (successful in 137 of 433patients [32%])Based on these results, can we state that PPS can prevent PiCM and should beroutinely recommended at least on an individualized basis? It could be argued thatthe success of physiological pacing is in part related to the use ofelectrophysiological parameters when performing this technique, which allows properidentification of the target region. Although this procedure is more complex andimplies a potential rise in costs, we propose this debate because we believe thatPiCM is secondary to artificially induced myocardial dyssynchrony by RV pacing. Whywould a patient with preserved physiological pacing of the ventricular syncytium develop 68][.In the context of AF, the Left Ventricular-Based Cardiac Stimulation Post AV NodalAblation Evaluation (or PAVE) study randomized 184 patients undergoing ablation ofthe AV node to receive CRT vs. PPS are needed to consolidate HBP as an initial strategyfor reducing PiCM. Several factors should be considered, including implant-relatedcomplications such as higher capture thresholds and undersensing and tool costs(dedicated leads and sheaths). In addition, some post-implantation factors are ofgreat influence, such as increased battery depletion and premature generatorreplacement (due to higher energy drain), among others. These aspects need to betested in a randomized, controlled setting before PPS can be widely used. There arecurrently several clinical trials comparing PPS vs. RV pacing and,more ambitiously, PPS vs. CRT. The results will demonstrate thetrue value of physiological artificial activation within the context of ACP and thepossibility of significantly reducing PiCM incidence.However, in addition to current studies, further robust clinical trials comparing RVpacing Artificially induced myocardial dyssynchrony by RV pacing leading to PiCM is arecently acknowledged condition. Its potential genesis occurs after RV pacinginitiation  and is probably associated with factors thatare prone to this condition (underlying heart disease or phenotype). It is caused byartificial ventricular dyssynchrony due to artificial electrical cardiac activationof the myocardium only. Its impact on ventricular function and association witharrhythmia and congestive HF should be considered. Therefore, sentinel biomarkerscould be used in the future to identify, prior to implantation, individuals who havea natural tendency to develop artificially induced dyssynchrony. In addition, strictclinical follow-up with evaluation of cardiac function and structure should beperformed periodically . Correction involves using biventricular cardiac pacing or the newphysiological alternatives, via PPS (direct His bundle or left bundle activation),to minimize ventricular dyssynchrony.


Microinvasive cardiac surgery includes procedures performed off-pump, on the beating heart, with limited or absent skin incision, and those that rely on live imaging techniques. Transapical off-pump beating heart neochordae implantation allows the repair of severe mitral valve regurgitation due to leaflet prolapse or flail with live three-dimensional echo guidance. This procedure has shown good results for up to 5 years and can be considered as a valid alternative to conventional surgery in selected patients with high prediction of success based on clinical and anatomical considerations. The aim of this review is to describe the devices, indications, patient screening process, clinical and echocardiographic results, and future perspectives of this procedure. The difference between minimally invasive and microinvasive cardiac surgery is that the former always needs cardiopulmonary bypass, cardioplegic arrest, and general anesthesia while the latter can be carried out off-pump, on the beating heart, and with local anesthesia only. Examples of microinvasive cardiac surgery are transcatheter aortic valve implantation (TAVI) and edge-to-edge transcatheter mitral valve repair. These procedures mimic conventional cardiac surgery operations without the need for extracorporeal circulation, cardioplegic arrest, and opening of cardiac cavities and can be carried out with a microinvasive approach. Transapical microinvasive mitral valve repair with neochord implantation (NC) was introduced into clinical practice in 2012. This procedure consists in correcting mitral leaflet prolapse by positioning, through transapical access, one or more artificial chordae, and by pulling them under live 3D TEE guidance. There used to be two commercial devices: NeoChord DS1000  and Harpoon . Since the latter has been recently withdrawn from the market and is no longer available for clinical use, in this article, we will mainly focus on the NeoChord device.This article will discuss the indications and contraindications for NC, patient selection, technical aspects, learning curve, clinical and echocardiographic outcomes, and future perspectives.1.1.must be treated surgically when the results are durable, when the patient is symptomatic, operable, and not high risk, and when the patient has no symptoms but the left ventricle is dysfunctional (LVESD > 40 mm and/or LVEF < 60%). Otherwise, surgery should be considered in asymptomatic patients with normal left ventricular function and atrial fibrillation secondary to mitral regurgitation or pulmonary hypertension (PAPs at rest >50 mmHg) or in low-risk asymptomatic patients with normal ventricular function and significant left atrial dilatation (volume index >60 ml/m2 or diameter >55 mm)  . Current5 mm . Cu1.2.Since the introduction of this new technology, patients can be divided into four groups according to regurgitating MV anatomy: “type A” with isolated central posterior leaflet flail/prolapse, “type B” with posterior multi-segmental flail/prolapse, “type C” with anterior or bi-leaflet prolapse/flail, and “type D” with paracommisural flail/prolapse or any significant leaflet or annular disease such as calcification , 7. Thisper se because, if leaflet tissue is abundant, LAI will still be in the feasibility range.Another important parameter for patient selection is the leaflet-to-annulus index (LAI). LAI is calculated as the ratio between the sum of the height of the anterior and posterior leaflet and the anteroposterior diameter and represents the amount of excess leaflet tissue that can potentially be used to recreate and correct leaflet coaptation . The cutAnother inclusion parameter focused on the tissue is the gap ratio which is defined as the ratio of the height/length of the prolapsing segment of the posterior leaflet to the gap between the coaptation surface of the anterior leaflet and the hinge point of the base of the posterior leaflet, measured at the peak systole. The cut-off is a gap ratio of 1.5:1 or more in order to have adequate posterior leaflet tissue to allow sufficient coaptation and effective abrogation of mitral regurgitation after repair  11)..11).In a study published in 2019, Colli et al. analyzed the possible mechanisms of recurrent regurgitation after neochord implantation. In total, 52 patients with recurrent moderate or severe MR were considered as Not Expected Surgical-Like Results (NESLR)-Redo and NESLR-MR2 (respectively reintervention or moderate MR 2+). They also divided the patients by onset of the regurgitation and by jet orientation and direction. After that, the authors analyzed the specific mechanisms of NESLR. Among the key points responsible for recurrent regurgitation, patient selection (17.3%), technical issues (28.8%), progression of baseline disease (15.4%), left ventricle reverse remodeling (1.9%), excessive over-tensioning (35.8%), and PML curling (30.8%) were identified. Detailed evaluation of valve anatomy  and a badly calculated LAI were the main problems occurring during patient selection. Furthermore, in this and in other studies, cases of neochord rupture were reported. Reasons can be mainly related to prolonged friction between different materials , excessive over-tensioning, and inadvertent neochordae damage during intraoperative manipulation but no clear data to assess this issue is available , 13.Exclusion criteria for NC implantation through a transapical approach are previous left chest surgery, pleural disease , active The biggest concern related to NC is the lack of annular stabilization which is a well-established predictor of repair durability in conventional surgery. However, many echocardiographic analyses showed, during NC follow-up, positive modifications of the valve and of the left ventricular geometry, and in our experience with trans-apical NC, failure has never been related to annular dilatation , 15. Thi1.3.The device consists of a single-use, hand-held device designed to load and deploy ePTFE sutures through exchangeable cartridges and a tethered leaflet verification display that confirms leaflet capture in the distal clamp of the instrument through four fiber optic lights that turn from red to white. During the operation, a stand-by cardiopulmonary bypass machine is recommended. The patient is under general anesthesia, mechanically ventilated through a double-lumen endotracheal tube, and rolled onto their right side in order to better expose the LV apex. The surgeon performs a left anterior mini-thoracotomy in the fifth intercostal space. After the left lung is excluded, the correct LV access site is identified by pushing one's finger 2–3 cm laterally and posteriorly from the true apex under 2D-TEE imaging. The correct identification of the entry site allows one to face the MV directly with the delivery system and to navigate through the subvalvular apparatus safely. Two concentric purse-string sutures of 2–0 MH polypropylene are placed in a crown-like manner with 4–5 large custom-made Teflon pledgets. Recently, we moved towards a more simple set-up with two perpendicular apical mattress sutures. Heparin is then given at a dose of 100 UI/Kg to reach an ACT of >300 s In the meantime, the instrument is loaded with one ePTFE suture and its specific needle. The surgeon performs transapical ventriculotomy with an 11 blade scalpel and prepares the entry site with a closed long straight clamp. When the device enters the LV, the purse strings are slightly tightened to reduce blood leakage. The NeoChord DS1000 is directed towards the left atrium with TEE guidance, avoiding the subvalvular apparatus by keeping the instrument under the A2-P2 segment. Once the mitral valve is passed, echocardiography imaging switches from 2D to 3D and the device is moved towards the prolapsing leaflet. When an appropriate position has been reached, the jaws of the device are opened, and the leaflet is grasped; the grasp is successful if all four fiber lights on the optic monitor turn from red to white. At this moment the surgeon keeps a firm hold of the device and carefully pushes the needle through the leaflet. Then the needle is retracted until the suture loop exits the instrument and the device is pulled out from the ventricle with the jaws opened while the two ends of the suture are gripped manually. The surgeon applies tension to the neochord and a girth hitch knot is secured to the leaflet, locking one head of the suture on the valve segment while the two ends remain outside of the LV. Additional chordae can be added by repeating the procedure in order to achieve maximal competence of the mitral valve . When a satisfactory number of chordae are applied, the apical purse string is tied, and an “eye needle” is used to pass through a round rigid Teflon pledget (big enough to cover the ventriculotomy) and all the neochordae. The pledget is then fixed with a 4-0 prolene suture over the ventriculotomy and tourniquets are placed over every neochord. Neochordae tensioning is then performed under TEE guidance in order to achieve good leaflet coaptation , 17. RevPosterior access is recommended to achieve more physiologic chordal implantation and well-distributed tension over the chordae and the leaflet edge .1.4.The Harpoon Mitral Valve Repair System (H-MRS) is composed of a 12-Fr introducer, with a hemostatic valve, and the delivery system  is characterized by an atraumatic end effector at the distal end which can stabilize the device on the ventricular side of the mitral valve leaflet at the targeted implantation site. Access is similar to the NC one in the fifth intercostal space. Once the introducer is inserted in the LV apex, the delivery system is directed toward the ventricular side of the prolapsed leaflet segment. The device is then steered under the leaflet target point and the leaflet is stabilized on the tip of the instrument, the needle is engaged, and the knot (double-helix knot) is deployed . The knot position is assessed by 3D TEE imaging and a minimum of 3 chordal pairs is recommended to distribute the tension. The rest of the procedure  is similar to NC , 11 Fig.α = 0°, to three more anterior access sites, with reference angles equal to 20°, 40°, and 50°. They found that when treating FF prolapses with a NeoChord device, a more anterior LV access site provides larger final displacement values but, on the other side, it has only a small effect on contacting-area, and it is related to tensioning forces and leaflet stress values that can be twice as high compared to those obtained for the posterior LV access site in the FF model. So, with posterior access sites, the risk of leaflet tearing is lower. When they considered the H-MRS, they found out that this device is less affected by the angle for B and FF prolapse. They concluded that (1) the NeoChord device seems to be a preferable solution for reaching the contacting area and maintaining operative leaflet stress if used with a posterior entry site; (2) the H-MRS, although having greater values in terms of tensioning force and leaflet stress, can experience better results if used with an anterior access entry site; (3) for FED prolapse the leaflet sticking point is determinant on the effective restoration of the valve, likely due to the small amount of tissue present in this type of prolapse; (4) there is evidence of contact between anterior leaflet and artificial chordae when the strings are implanted anteriorly , forma frusta (FF), and fibroelastic deficiency (FED). They studied different scenarios with different trajectories and different numbers of ePTFE implanted, i.e., from a posterior access site  corresponding to a reference angle teriorly .Another important point to consider during this kind of surgery is collaboration between team members. In particular, transesophageal echocardiography represents the “eyes” of the surgeon and a strong interaction with the echo physician (anesthesiologist or cardiologist) is crucial , 20.1.5.Like all new techniques, there is a learning curve for NC that requires the acquisition of new technical skills and familiarization with live three-dimensional echocardiographic imaging. In a study by Colli et al., three phases of experience were identified: an initial “learning phase” (first 20 procedures), a second “intermediate phase” and a final “expert phase”. The first phase is characterized by a relatively high actual probability of failure (25%) while the last phase demonstrated a decrease to 5%. However, the cumulative sum control chart (CUSUM) analysis never reached the alarm line beyond which the number of deaths or ineffective procedures would be too high. This condition was also respected at the beginning of the study. This analysis found that a surgeon should complete about 50 procedures in order to reach the “good performance period”. Obviously, this learning curve could be further reduced with a higher amount of proctored procedures and ad-hoc training on ex-vivo programs with simulators , 10, 21.1.6.1.6.1.p < 0,05) in the systolic anteroposterior diameter, TAPSE, SPAP, indexed left atrial volume, indexed left ventricular end diastolic volume, and left ventricular ejection fraction. At 1 year follow-up, 80.3% of patients presented MR ≤ mild, while 19.7% had MR ≥ moderate. They also observed a reduction of AP diameter, reduction of annulus circumference, reduction of MV area, and reduction of the aorto-mitral angle. These parameters seemed to be protective factors against the recurrence of MR greater than mild. All these changes can be justified by an acute reduction of MR, resulting in an immediate cessation of volume overload in the left atrium and left ventricle that consequently modifies MV geometry over time  during the first month. Acute procedural success (APS) was defined as the placement of at least one neochord and reduction of MR to <2+ and this was achieved in 86.7%; at 30 days 58.6% maintained performance success. This was the first trial that demonstrated the feasibility, safety, and efficacy of off-pump transapical implantation of neochords using the NeoChord DS1000. Since this trial, many studies have been conducted over time in order to better understand and improve this new technology and its outcomes. Looking at the acute intraoperative echocardiographic changes, Colli et al. retrospectively analyzed the baseline and early postoperative 3D TEE echocardiography of 66 patients. Immediately after the procedure, they observed a significant reduction  but in patients with type A anatomy, freedom from severe MR between the two groups was similar . Likewise, freedom from reoperation was lower in the NC group  but in type A patients, it appeared to be similar between the NC and CS groups . The study also could not find any difference in terms of mortality and major postoperative complications between the 2 groups but it showed that all patients had significant improvement in NYHA functional class during follow-up  in 372 patients showed interesting data. The study demonstrated the importance of patient selection and its influence on postoperative outcomes in terms of freedom from moderate and severe MR and from reoperation. Freedom from severe MR at follow-up was worse in patients undergoing NC vs. conventional surgery ] and cumulative incidence of severe residual MR  .1.7.In the last decade, microinvasive mitral valve repair with transapical neochordae implantation has proven to be promising in clinical practice. These procedures allow the surgeon to preserve MV anatomy and to avoid the risks associated with extracorporeal circulation and cardioplegic arrest. They enable to repair the valve on the beating heart during a physiological cardiac cycle and to observe the surgical result in real-time. In the case of MR recurrence, if a conventional surgical operation is needed, there are no issues related to sternal reentry and a surgical repair is still feasible.Other chordal repair technologies are in their development process, in particular transeptal devices, with the aim to be as minimally invasive as possible and to be used in high-risk patients where other approaches are not feasible.There are many first-in-human reports available such as the first Mitral Chordal Repair using the transcatheter transeptal NeoChord NeXus System. In a high-risk 55-year-old man, two neochordae were implanted and the mitral coaptation was restored . At a 3-month follow-up, the patient had improved NYHA class and sustained MR reduction and anchor stability. This device has the same advantages as its surgical counterpart and it also has the potential to address both anterior and posterior leaflet pathologies but further cases are required to confirm these initial results .Mitralstitch is a transapical device for beating heart chordal implantation. The pledgeted sutures are implanted directly in the body of the leaflet without a direct suture loop or knots. This device has also a specifically designed retrievable positioning device made of a nitinol frame that provides a precise grasping of the leaflet. The chordae are implanted under TEE imaging and not fluoroscopy. Another feature of Mitralstitch is that this instrument can perform an edge-to-edge procedure through a double leaflet chordal implant and following edge approximation by means of a locker. The results of the first-in-human study published this year by Wang et al. proved the safety and feasibility of this system. Ten patients with severe MR were enrolled and underwent the procedure. MR was reduced from severe to none or trace in five patients, and to mild in five patients at discharge. One patient also received edge-to-edge repair by locking two neochordae. The safety and efficacy endpoint of the study was achieved in all patients at a 1-month follow-up. At 1 year, six patients had mild MR, three had moderate MR, and one had severe MR recurrence and underwent surgical repair , 29.Mistral Chordal Repair is composed of a 12-Fr off-the-shelf catheter and 7.5 Fr delivery system which consists of a 3D nitinol spiral-shaped atraumatic wire inserted from the femoral vein via a transseptal approach to encircle the native mitral chords from both leaflets to bring them together. Chordal approximation is obtained with the rotation of the system. The catheter guide is inserted into the left ventricle via the transfemoral vein and transeptal puncture and then the spiral is released. Under TEE imaging, the surgeon rotates the system in order to catch both leaflet's native chordae and then keeps rotating it in order to move the chordae closer together. When the optimal competency of the valve is achieved, the applicator catheter is retrieved from the ventricle releasing the spiral in the desired final position . To the ChordArt is a transcatheter mitral repair system and it is made of three components: a distal ventricular/papillary muscle anchor, a proximal nickel-titanium anchor for leaflet securement, and the ePTFE chordae. The procedure is performed through a thoracotomy, but it can be also translated into a percutaneous transfemoral-transeptal delivery system. The leaflet is grasped at the P2 level and is punctured, then the distal anchoring system is delivered to the papillary muscle. In 2021, a study by Weber et al. was published reporting 2-year results. Five patients with symptomatic severe primary degenerative MR were enrolled and treated through a transseptal approach. APS was achieved in all patients and residual MR was trace or absent. MR less than 1+/4 was maintained over 2 years of follow-up. No dehiscence, detachment, or dislocation of the implanted ChordArt devices was observed. The authors also observed a positive remodeling of the left ventricle: the LV end diastolic diameter decreased during the whole follow-up period in comparison to the baseline condition, especially at discharge and 1-month follow-up. The LV end systolic diameter also decreased during the entire follow-up period in comparison to the baseline condition, with an initial mild increase at discharge. Left atrial volume decreased during the follow-up period in comparison to discharge. No major adverse events were reported either during the intervention or during the follow-up period .V-Chordal is a surgical transcatheter technology allowing on-pump chordal implant with off-pump beating heart length adjustment via trans-atrial approach, through a left atrial roof incision. Efficacy and feasibility in animal experiments were demonstrated , 32 and Pipeline is a transfemoral transseptal chordal repair system for off-pump beating heart chordal replacement. The device has a deflectable guide catheter, a delivery catheter, and four parts that allow chordal implantation: leaflet pledgets with Gore-Tex sutures, a suture lock, a ventricular anchor, and a suture cutter. In 2020, the first-in-human neochord implantation was reported in a 56-year-old patient with symptomatic P2 prolapse and NYHA III. The procedure was successful with echocardiography and fluoroscopy imaging throughout the surgery. The patient had an uneventful immediate postoperative course but before discharge, recurrent asymptomatic MR due to partial anchor displacement was observed and the patient underwent surgical mitral valve replacement .CardioMech is developing a percutaneous solution for artificial chordae implantation. The device is made of a gripper element housing a self-expandable folded anchor made of memory-shape material. When the leaflet is grasped the anchor is unfolded and secured to the leaflet. The system also presents a self-expandable folded papillary anchor made of shape memory metal. The chord length is adjustable under real-time echocardiographic guidance. This technology is in a phase of clinical trials (Identifier: NCT04820764) that is scheduled to be completed in 2026. There is one case report in 2021 of the first-in-human transcatheter transeptal procedure in an elderly patient with severe symptomatic MV regurgitation. The procedure was successful, the regurgitation from severe became mild, and the patient was discharged home the next day .2.Transapical off-pump beating heart neochordae implantation is a microinvasive alternative to conventional surgery in patients with severe primary MR. In well-selected patients, this procedure has been shown to be safe and to provide good outcomes for up to 5 years in terms of recurrence of MR and freedom from reoperation. Accurate patient selection based on careful echocardiographic evaluation of anatomic characteristics together with a well-trained surgical team is crucial to obtain good early and long-term clinical and hemodynamic outcomes. At present, there is only one CE-marked device for this operation: NeoChord DS1000. Transapical neochordae implantation has demonstrated that restoring mitral competency in the beating heart by implanting artificial chordae is feasible. As a consequence, several trans-septal devices aimed at implanting neochordae through a completely percutaneous approach are now under development and in the initial investigation phase.


It has been a scarcity of evidence regarding differences in left ventricular (LV) and left atrial (LA) size and strain changes across stages of chronic kidney disease (CKD) and which echocardiographic parameters could be utilized to predict the decline of glomerular filtration rate (GFR).This study aimed to evaluate the alterations of LV and LA strain across the reduction of renal function and potential echocardiographic parameters which could be correlated with the GFR decline among patients with CKD.A cross-sectional study was conducted on 169 CKD patients at Bach Mai General Hospital, Hanoi, Vietnam from April to November 2022. Demographic, clinical and laboratory characteristics of patients were collected. Transthoracic echocardiography was performed to measure LV and LA size and strains. Jonckheere-Terpstra test was used to measure the tendency of change. Multivariate linear regression models were performed to find associations between different echocardiographic parameters and renal function reduction.β = 0.068), ejection fraction (β = 0.112) and left atrial reservoir (β = −0.077) were associated with reduced GFR.The number of patients with CKD stages 1, 2, 3, 4, and 5 was 21 (12.4%), 28 (16.6%), 27 (16.0%), 22 (13.0%) and 71 (42.0%), respectively. CKD severity was positively associated with LV diastolic and systolic diameters, LV mass, E/e' ratio, and maximal tricuspid regurgitation velocity (TR max), and negatively correlated with the LV global longitudinal strain. Higher severity of CKD stage was associated with higher LA diameter, LA strain, and volume in four and two-chamber views, and lower LA reservoir and conduit function. Left ventricular mass (Left ventricular mass, ejection fraction, and atrial longitudinal strain by STE should be done at the earlier stages of CKD patients for better follow-up of GFR decline. This cardiomyopathy has distinctive phenotypes with important changes such as left ventricular (LV) enlargement, left atrial (LA) dilatation, diastolic dysfunction, and decreased myocardial deformation which could indicate myocardial fibrosis –7. In li2.2.1.A cross-sectional study was conducted at Bach Mai General Hospital, Hanoi, Vietnam from April to November 2022. All patients who were diagnosed with CKD according to KDIGO 2012 criteria , and vis2.2.When performing transthoracic echocardiography (TTE), information about age, gender, blood pressure, heart rate, and body composition was collected. Laboratory testing results and clinical information were simultaneously obtained from a hospital's electronic database. TTE was done using a Vivid E95 ultrasound system  and an M5S transducer with a frequency of 1.5–4.5 MHz. To avoid circadian effects, all ultrasound tests were carried out by qualified doctors in the late afternoon on the same day. Echocardiographic exams were performed following the scheduled hemodialysis session .Based on the most recent recommendations of the European Association of Cardiovascular Imaging and the American Society of Echocardiography, cardiac chamber measurements were performed . The dimE wave), the peak late diastolic velocity of the mitral annulus (e' wave), the ratio of the two (E/e' wave), and Isovolumic relaxation time (IVRT) were all measured. Determination of LV diastolic inflow using Doppler techniques was conducted on the apical four-chamber section by placing the sample volume at the tip level. E and A peak velocities along with their respective E/A ratio and E-wave deceleration time were computed. By using TDI, the early (e') diastolic velocities were evaluated at the septal and lateral insertion sites of the annulus of the mitral valve. The average value from the two measurements was then calculated . The modified Simpson's approach was used to compute LV ejection fraction (LVEF). The left atrial anteroposterior diameter (LAd) was evaluated from the parasternal long-axis view. After manual adjustment, LA volume was automatically computed and indexed to BSA. Pulmonary artery systolic pressure (PAPs) was determined by using tricuspid regurgitant (TR) jet velocity, inferior vena cava diameter, and the percentage of collapsibility into the formula:lculated .Apical four-chamber and two-chamber pictures were recorded during breath hold for the speckle tracking analysis using a reliable TTE recording at a frame rate of 60–90 frames per second. In each view, three consecutive cardiac cycles were acquired for offline analysis using certain software . Trained medical professionals measured the LV and LA speckle tracking parameters. GLS was evaluated following seven steps according to the guideline of Negishi et al. .P wave on the ECG  and 18.8% (inter-observer), and 9.4% (intra-observer) and 13.7% (inter-observer), respectively.2.4.p-value <0.05 was considered statistically significant.Statistical Package for Social Sciences (SPSS) version 25 was used to analyze the data. For categorical variables, descriptive statistics were presented as frequencies and percentages. Continuous variables were presented as mean (SD), or median (interquartile range-IQR). The Jonckheere-Terpstra test was applied to detect trends in continuous variables across the stages of CKD. The difference of categorical among the stages of CKD was evaluated using the Chi-square test. Multivariate linear regression was performed. No multicollinearity was found in the model. A 3.p < 0.001), higher systolic blood pressure (mmHg) (p < 0.001) and higher diastolic blood pressure (mmHg) (p < 0.001) and different medication used  (p < 0.001).Among 169 patients, regarding clinical characteristics, p < 0.001), a higher concentration of serum urea (mmol/L) (p < 0.001) and creatinine (mmol/L) (p < 0.001). In terms of hematologic findings, lower hemoglobin (g/L) and RBC results (T/L) (p < 0.001) were related to more severe stages. Patients at the later stages had lower cholesterol levels (mmol/L), higher plasma albumin (g/L), higher plasma protein (g/L) and higher ferritin (ng/ml) (p < 0.05). No statistical difference in serum triglyceride, HDL-C, LDL-C, transferrin, and urine protein was found among CKD stages.According to laboratory testing characteristics, p < 0.05). The differences in GLS (%) (p < 0.001) among different CKD groups were also observed.p < 0.001), LA strain in four-chamber view  (p < 0.001), LA strain in two-chamber view  (p < 0.001), LA volume in four-chamber view  (p < 0.001), LA volume in two-chamber view  (p < 0.001), LA volume index  (p < 0.001), LA volume before A wave  (p < 0.001). The significant reduction in the LA reservoir strain  (p < 0.001), while the remarkable increase (less negative) was observed in the LA conduit strain  (p < 0.001) among different CKD groups. The alteration of LASct across CKD stages was not significant (p = 0.2144).The analysis of LA volume and strain in β = 0.068; p = 0.022), LV mass  and LASr  were found to be significantly correlated with GFR reduction.4.This study contributed to the current body of literature about the progressive reduction of LV and LA strain and increase in volume according to the CKD stages. By speckle tracking echocardiography, the current study also found the associations between left atrial reservoir function assessed (LASr), left ventricular ejection fraction (LVEF) and left ventricular mass index (LV mass) and the decline of kidney filtration function (GFR).Left ventricular hypertrophy, dilatation, and dysfunction are the most common cardiac abnormalities in CKD patients . PreviouThe LV pathological changes may cause LA function impairment as there is a close connection between the two chambers. The left atrium is a more sensitive chamber to fluid overload and increased LV filling pressure among CKD patients . Left atP wave as the time reference for defining zero-baseline for both LV and LA strain curves in comparison with the use of ventricular end-diastole, further research that compares both approaches should be elucidated. In addition, 2D-STE analysis has several intrinsic limitations, such as the dependency on the temporal stability of tracking patterns, the need for high-quality grey-scale images for reducing inter- and intra-observer variability of tracking data and finally a relevant intervendor variability. Finally, taking into consideration the fact that individuals with advanced stages of CKD demonstrated a higher likelihood of presenting with more severe hypertension, it is plausible that the efficacy of hypertension treatment could influence the outcomes of our study.Our study has several limitations. This study was unable to show changes in LV and LA over time due to its cross-sectional design. Secondly, the small sample size in this study hindered the ability to apply findings to the general population. In addition, the overwhelm of patients in CKD stage 5 might cause selection bias. Thirdly, although no difference in the selection of 5.LV and LA volume and strain assessed by speckle tracking echocardiography were associated with advancing CKD stages. LV mass, LV ejection fraction and LA reservoir might be used to suggest the decline of kidney glomerular filtration function. They could be used at the earlier stages of CKD patients for better follow-up of GFR decline.


This study aimed to investigate the ventricular mechanical relaxation pattern and its clinical influence in patients with ST-segment elevation myocardial infarction (STEMI).Echocardiography was performed to measure mitral and tricuspid diastolic opening times. Left ventricular diastolic mechanical delay (LVMDd) was defined as diastolic filling of the right ventricle earlier than that of the left ventricle, and right ventricular diastolic mechanical delay (RVMDd) was defined as the right ventricular diastolic filling later than left ventricular filling.P = 0.017). Those with RVMDd exhibited significantly lower left ventricular global longitudinal strain , global work index  and global constructive work . Mitral deceleration time significantly decreased , and the ratio of early mitral inflow to early mitral annular velocity (E/E’) significantly increased  in the RVMDd group. Logistic regression analysis showed that age , brain natriuretic peptide level  and mitral E/E’  were independently associated with RVMDd.Among 152 patients with STEMI, 100 (65.8%) had LVMDd, and 47 (30.9%) had RVMDd. In-hospital complications were significantly increased in patients with RVMDd (61.6% vs. 41.0%, Delayed right ventricular filling is related to more severe left ventricular systolic and diastolic dysfunction in STEMI patients. More attention should be paid to patients with RVMDd to prevent adverse events during hospitalization. Ventricular mechanical dyssynchrony is a major contributor to the deterioration of heart failure (HF) . CardiacE) was less than that of the mitral valve (Q-MVE), and we defined this differences as left ventricular diastolic mechanical delay (LVMDd)  and higher levels of brain natriuretic peptide (BNP)  at admission when compared with those in the LVMDd group. There was no difference in the pre and post-PCI data, culprit vessels, or thrombolysis in myocardial infarction blood flow. However, the incidence of total complications in the hospital, including acute HF, arrhythmia, stroke, mechanical complications, use of circulatory support devices or ventilators, re-infarction, and death, significantly increased in the RVMDd group .Table P = 0.035), GWI  and GCW  when compared with those in the LVMDd group. Moreover, two important indicators of diastolic function also showed significant differences: EDT significantly decreased , and E/E’ significantly increased  in the RVMDd group. Figure The echocardiographic characteristics and global values of the LVMW indices between the two groups were shown in Table P = 0.001), BNP  level and mitral E/E’  were independently associated with RVMDd.Logistic regression analysis was performed to identify predictors of RVMDd. Variables with P < 0.1 in univariate analysis were subsequently entered into the multivariate model. Clinical data included age, BMI, history of hypertension, SBP at admission, Killip classification, TnI, BNP, and left anterior descending (LAD) coronary artery as the culprit vessel, and echocardiographic data included LVEF, GLS, mitral E/E’, GWI, GCW and GWE. A comprehensive multivariable analysis including clinical and echocardiographic data was performed and the results were presented in Table In this study, we explored the ventricular diastolic mechanical sequence in patients with STEMI. LVMDd, an indicator of earlier RV filling than LV filling, was found in 65.8% of patients, whereas RVMDd, an indicator of later RV filling than LV filling, was found in 30.9% of patients. Compared with patients with LVMDd, those with RVMDd had a more severe condition: a lower percentage of Killip I classification and higher values of TnI and BNP levels. Moreover, the incidence of complications in the hospital was substantially higher in patients with RVMDd than in those with LVMDd.Our previous study confirmed a highly consistent diastolic filling pattern (LVMDd) in the normal population, while the fraction of RVMDd increased significantly in patients with HF . The venOur data suggested that age and BNP level were independently associated with RVMDd. In STEMI patients, increased age and BNP level were related to a more severe condition, consistent with the idea that the occurrence of RVMDd might be an indicator of more severe myocardial dysfunction. In addition, E/E’ was significantly increased in patients with RVMDd and independently associated with RVMDd presence. Echocardiographic E/E’ was an important indicator of ventricular diastolic function . Left veThe coordinated contraction and relaxation of the left and right ventricles are essential for global heart performance. Asynchronous ventricular mechanical activation in various disease states affects the overall ventricular pump function due to inter- and intra-ventricular asynchrony. At present, the medical treatment of resynchronization mainly focuses on systolic synchrony, such as CRT treatment of heart failure after myocardial infarction. The synchronization in diastole is rarely concerned. But the coronary blood flow perfusion is mainly achieved in diastole. Therefore, the presence of RVMDd may affect the LV myocardial perfusion in STEMI patients. Inter-ventricular dyssynchrony assessment is critical to optimize inter-ventricular delays (V-V delays) in CRT settings. Optimal timing of V-V delays improves ventricular filling capacity and stroke volume, resulting in the reversal of LV remodeling and an improved prognosis , 23. AcuOur study was limited by the relatively small number of participants included and the lack of follow-up data. We could not determine the long-term prognostic value of this inter-ventricular mechanical sequence in STEMI patients. QRS durations according to both groups were not collected for either group. The related variables and prognostic values of the severity of inter-ventricular mechanical delay required further investigation.Our study explored the mechanical diastolic sequence of the left and right ventricles in STEMI patients. RVMDd occurrence was associated with more severe impairments in myocardial function and increased total complications in the hospital. Mechanical dyssynchrony assessed by echocardiography is a simple but potential tool to detect early myocardial performance impairment and should be considered for monitoring therapeutic response during routine follow-up in these patients.


Soluble (s)ST2 has been proposed as a useful biomarker for heart failure (HF) patient management. Myocardial damage or mechanical stress stimulate sST2 release. ST2 competes with a membrane bound receptor  for interleukin-33 (IL-33) binding, inhibiting the effects induced by the ST2L/IL-33 interaction so that excessive sST2 may contribute to myocardial fibrosis and ventricular remodeling. Compared to natriuretic peptides (NPs), sST2 concentration is not substantially affected by age, sex, body mass index, kidney function, atrial fibrillation, anemia, or HF etiology, and has low intra-individual variation. Its prognostic role as an independent marker is well reported in the literature. However, there is a gap on its use in combination with NPs, currently the only biomarkers recommended by European and American guidelines for HF management. Reflecting the activation of two distinct biological systems, a benefit from the use of sST2 and NP in combination is advocated. The aim of this review is to report the current scientific knowledge on sST2 in the acute and chronic HF settings with a particular attention to its additive role to natriuretic peptides (NPs). Quantifying concentrations of circulating biomarkers plays a major role in most cardiovascular (CV) diseases, including heart failure (HF) .An ideal biomarker in HF should be (1) measured non-invasively and at low cost, 2) highly sensitive to allow for the early detection of the disease, 3) unaffected or minimally affected by comorbid conditions, and 4) responsive to treatment effects [ highly s unaffect responsiBeyond their well-established diagnostic role in acute and chronic setting, the role of BNP and NT-proBNP in risk stratification is gaining more momentum in clinical practice. In fact, low values of NPs at discharge reflect the achievement of greater decongestion, which correlate with a lower risk of re-hospitalization and death. In addition, the pre-discharge value can be used to determine the intensity of monitoring and the timing for follow-up visits .However, there are important limitations to natriuretic peptide (NP) testing in HF. Most important is the impact caused by conditions commonly associated with HF such as atrial fibrillation (AF), kidney dysfunction and obesity, as well as a wide range of cardiac and non-cardiac abnormalities associated with an increase in parietal tension without necessarily being linked to fluid retention . NP concNumerous other biomarkers have been evaluated in HF and are under investigation. Some of these have been more convincing and are used in some clinics today. Of particular prominence is soluble ST2 (sST2) , which wThe aim of this review is to update the current knowledge on sST2 in acute and chronic HF with a particular attention to its additive role to NPs.ST2 is a member of the interleukin (IL)-1 receptor family , whose gThe literature mistakenly called ST2 a “suppressor of tumorigenicity 2”, when, in fact, the original name it was given was “growth stimulation expressed gene 2”, then renamed “serum stimulation-2”, as it was first discovered to function as a mediator of type 2 inflammatory responses .Its role as a cardiac marker was suggested in 2002 by Weinberg et al. , analyziThe cognate ligand of ST2 is interleukin-33 (IL-33), a cardiac fibroblast protein released by stromal cells in cardiac and extracardiac tissues. Depending on co-stimulatory factors, IL-33 can act either as a pro- or anti-inflammatory cytokine. At the cardiac level, the ST2L/IL-33 interaction initiates a complex cardioprotective biochemical cascade, which prevents cardiomyocyte hypertrophy, apoptosis, and myocardial fibrosis, thereby improving cardiac function. However, when the heart is subjected to damage or mechanical stress, cardiomyocytes and cardiac fibroblasts secrete sST2, which, competing with ST2L for the IL-33 binding site, antagonizes the cardioprotective effect, contributing to myocardial fibrosis and ventricular remodeling ,19,20.  Hence, tThe “inflammatory hypothesis” of atherosclerosis implies that the presence of inflammation favors the formation, growth, and, finally, the instability of atherosclerotic plaques, favoring the onset of cardiovascular events . The IL-p = 0.018), metastatic disease (p = 0.014), and was significantly correlated with the duration of the disease (p = 0.0017) [sST2 also appears to be involved in the pathogenesis of cancers, trying to counterbalance the tumorigenesis effect of IL-33/ST2, and could therefore be used for non-invasive diagnostic tests, as a prognostic marker and for treatment monitoring . For exa 0.0017) . Similar 0.0017) ,27.ST2L is a cell-surface marker of T helper type 2 (Th2) lymphocytes and, therefore, IL-33/ST2 has an essential role in immune regulation. As a result, it has been associated with diseases characterized by a predominantly Th2 response, such as asthma, pulmonary fibrosis, rheumatoid arthritis, collagen vascular diseases, sepsis, trauma, fibroproliferative diseases and ulcerative colitis . IL-33/SBeing a non-cardiac-specific biomarker, sST2 is less useful for diagnosing HF, but has proven helpful for risk stratification, both in chronic and acute settings . p < 0.001) [The vast majority of studies considered sST2 in the context of HF, whereas more limited and discordant data were published regarding sST2 concentrations in healthy individuals or at risk for developing HF . It has < 0.001) . This st< 0.001) . Further< 0.001) . Higher < 0.001) . While a< 0.001) . p for interaction 0.40), even after adjusting for NPs levels  [It is, however, important to highlight studies with neutral results. In a healthy general population from Finland including 8444 men and women, sST2 did not improve the long-term prediction of CV events including HF  . Similarctively) . More reIn acute HF (AHF), increased levels of sST2 appear to be linked to the peripheral release of pro-inflammatory cytokines by vascular endothelial cells and lung tissue in response to congestion and inflammation ,41,42. Ap = 0.33). The area under the curve (AUC) for sST2 was 0.62 , suggesting moderately low diagnostic utility [p < 0.001) [Currently, in this setting, the sST2 diagnostic value is controversial and merits further studies. Henry-Okafor et al. demonstrated among patients presented to the emergency department with signs or symptoms of AHF that sST2 was not significantly associated with the diagnosis of AHF in adjusted models  . p < 0.001) as well as in those with AHF . In another study of 1528 ADHF patients enrolled from the HF Center of Beijing Fuwai Hospital, sST2 concentrations were measured within 12 h of hospitalization for HF [p < 0.001). Patients in the fourth quartile of sST2 as measured with a high-sensitivity enzyme-linked immunosorbent assay (>55.6 ng/mL) had a higher rate of AEs if compared with patients with the lowest sST2 concentration quartile (≤25.2 ng/mL) , with a graded increase in AEs’ rates at 3 months, 1 year and 3 years according to sST2 quartiles. Cox regression showed that sST2 concentrations were significantly associated with the combined endpoint in univariable and multivariable analysis after adjustment for several variables, including NT-proBNP levels . Similarly, Pascual-Figal et al. [p = 0.005 in multivariable analysis). Using ROC analysis, the optimal cut-off points for the prediction of death were >65 ng/mL.In contrast with the diagnostic role, the prognostic role of sST2 has been described in several studies . In the n for HF . The conl et al.  conductep < 0.001), although this association was not significant after adjustments for NT-proBNP and the ASCEND-HF risk model. Subjects with persistently high (>60 ng/mL) sST2 levels at 30 days had higher 180-day death rates than those with lower sST2 levels . Lastly, in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial , sST2 wap < 0.01) and early ST2 changes independently predicted 1-year mortality  [Serial sST2 measurements during hospitalization are also recommended because they may provide a basis for enhanced clinical decision making and improve the accuracy of mortality prediction . In fact = 0.02) . Similar = 0.02) .p = 0.11). Therefore, currently, the use of sST2 is not recommended to guide medical therapy. As for the prognostic role, in ADHF, the current evidence recommends that ST2 concentration should be assessed at baseline  and after treatment to reflect therapeutic effectiveness, independent of repeated measurements of NPs [sST2 concentration tends to decrease after the initiation of HF treatment and from decongestion as a result of reducing the inflammatory picture, reducing the cardiotoxic mechanism and reducing mechanical stress and volemia . Thus, cs of NPs ,64,65. Is of NPs .The prognostic importance of sST2 in AHF was confirmed in a meta-analysis  of 4835 Based on the International ST2 Consensus Panel published in 2015, an sST2 ≥ 35 ng/mL value was recommended as a predictor threshold for a poor prognosis in AHF . Howevern = 250) than in those with HFpEF (n = 197) but elevated sST2 concentrations were associated with a greater mortality risk in both populations, even after adjusting potential confounders and NT-proBNP. Positive results in patients with HFpEF have also been shown more recently by Sugano et al. [Of note, the prognostic role of sST2 is consistent in both HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) patients, as demonstrated by Manzano-Fernández et al. , who proo et al.  and Shaho et al. . n = 4268), a single sST2 measurement yielded a prognostic value independent of age, HF etiology, LVEF, estimated glomerular filtration rate (eGFR), and the concentrations of other CV biomarkers, including NT-proBNP [Much as with AHF, the concentrations of sST2 represent a strong prognostic measure in chronic HF (CHF) . For exaT-proBNP . SimilarT-proBNP . In 2331T-proBNP , sST2 waT-proBNP . Several studies also provide evidence of a significant association between increased sST2 levels and outcome in HFpEF ,68,69. GAs previously mentioned, NPs have important limitations as they are affected by common comorbidities in patients with HF. AF and renal disease substantially increase the concentrations of NPs, while obesity is associated with lower NP levels . In addiBecause sST2 elevations reflect the activation of distinct biological systems compared with the NPs, there is a knowledge gap as to whether sST2 can provide additional prognostic information ,59. Multp < 0.001). For this reason, this triad of biomarkers, reflecting different facets of HF pathophysiology, has been included in the Barcelona Bio-HF calculator, a risk score that calculates the risk of all-cause death and/or HF hospitalization [Prognostic stratification in AHF can be further implemented through the addition of other biomarkers to sST2 and NPs, including high-sensitive cardiac troponin-T (hs-cTnT) . In factlization . p < 0.001), again indicating that the assessment of both sST2 and NT-proBNP is more effective in identifying a high-risk subgroup than individual assessments of either biomarker. Lastly, a post hoc analysis of the MUSIC (MUerte Súbita en Insuficiencia Cardìaca) study [p = 0.002) was more predictive of SCD than evaluating each biomarker separately. This combined variable added incremental prognostic value to the multivariable regression model. Only 4% of patients experienced SCD for neither sST2 nor NT-proBNP above the ROC-derived cut-off points; 34% for either of the biomarkers above; and 71% for both biomarkers above.Even among patients with CHF, the combined assessment of sST2 and NT-proBNP is more effective in identifying a high-risk subgroup than the individual assessment of both biomarkers ,56. Simia) study  analyzedsST2 is a strong independent prognostic marker in HF patients regardless of LVEF and NPs concentrations. Due to its secretion following independent pathways, its role appears useful to improve risk stratification beyond NPs. Up to now, however, the available evidence has come from non-randomized studies, thus not enabling any mention of it in recent ESC3 and ACC/AHA4 guidelines on HF management, while the 2013 ACC/AHA83 clinical practice guidelines gave a Class IIb recommendation for sST2 measurements only in CHF for the purpose of risk stratification and prognostication. Further studies are therefore needed in order to frame this promising biomarker in the management of HF.


Over the last several years, the use of biomarkers in the diagnosis of patients with heart failure (HF) has skyrocketed. Natriuretic peptides are currently the most widely used biomarker in the diagnosis and prognosis of individuals with HF. Proenkephalin (PENK) activates delta-opioid receptors in cardiac tissue, resulting in a decreased myocardial contractility and heart rate. However, the goal of this meta-analysis is to evaluate the association between the PENK level at the time of admission and prognosis in patients with HF, such as all-cause mortality, rehospitalization, and decreasing renal function. High PENK levels have been associated with a worsened prognosis in patients with HF. Nearly 64.3 million individuals worldwide are living with heart failure . Heart fOver the past several decades, the subject of biomarkers has garnered extensive research in the routine care and management of patients with heart failure. Circulating cardiac biomarkers are significant for the diagnosis, management, and prognosis of cardiac disorders, particularly heart failure. The current approved biomarkers for HF are natriuretic peptides such as B-type natriuretic peptide (BNP) and the N-terminal fragment of its prohormone (NT-proBNP) . FurtherSeveral studies have been evaluated, ranging from the primary molecular mechanisms to clinical studies of PENK that suspect a link between increasing PENK and worsening cardiac function. Various aspects ,9,10,11 A systematic literature search from the MEDLINE (via PubMed), EMBASE (via Scopus), and Cochrane Database of Systematic Reviews databases was conducted for studies up until September 2021. The purpose is to identify studies that measured the associations between plasma PENK levels and prognostic values such as all-cause mortality, rehospitalization, and worsening renal function in HF patients. Two investigators (N.S. and K.L.) independently gathered the systematic literature review using a search strategy that included the terms ‘proenkephalin’ and ‘heart failure,’ as stated in the The qualified studies must be cross-sectional, case-control, or cohort studies that assess the relationship between plasma PENK levels and prognostic values in HF patients. Case reports and case series were excluded from the study. They must give the estimates of effects including the odds ratios (ORs), relative risks (RRs), or hazard ratios (HRs) with 95% confidence intervals (CI). The inclusion of studies was not restricted by sample size or population ethnicity. Any disagreements concerning study choices were settled through collaborative conversation. As indicated in The following information was collected from each study using a structured data record form: title, year of the study, name of the first author, publication year, country where the study was conducted, patient baseline characteristics, demographic data, and method used to identify heart failure patients and measure the plasma PENK level. In addition to the previously mentioned data collection, classifications of the PENK level in each group and definitions of all-cause mortality, rehospitalization, and worsening renal function were also collected. Adjust effect estimates using 95 percent confidence intervals and factors that were modified in the multivariable analysis were used in the study.According to the literature review ,9,10,11 According to the literature review, worsening renal function is defined as a decrease of more than 25% in the estimated glomerular filtration rate (eGFR) compared to baseline  or an inp < 0.1 or I2 > 25%), the DerSimonian and Laird technique was used; otherwise, an inverse-variance fixed-effect model was utilized [The R program was used to analyze the obtained data. Adjusted point estimates from each study were calculated using DerSimonian and Laird’s generic inverse variance technique, which assigned a weight to each study based on its variance . A randoutilized . Subsequutilized .p = 0.11), indicating that the publication year had no effect on the effect size.The sensitivity analysis is computed using a mixed-effect model. The moderator test was statistically insignificant , a high level of PENK was substantially related with a greater incidence of all-cause death. Six studies ,9,10,11 2 = 0%; Two studies ,10 inves2 = 0%; Three studies ,10,11 exApart from HF prognoses, the studies revealed a significant correlation between patient variables  and plasma PENK levels. Furthermore, plasma PENK levels are correlated with numerous laboratory findings  and imaging data . In this meta-analysis, we observed that plasma proenkephalin levels were significantly associated with HF outcomes such as all-cause mortality, rehospitalization, and worsening renal function. When compared to patients with normal plasma PENK levels, those with high plasma levels had a 72 percent increased risk of all-cause mortality and a 51 percent increased risk of rehospitalization. Furthermore, there is a 1.57-fold increase in the likelihood of an incident worsening renal function in HF.In the past ten years, there have been an increasing number of studies describing the mechanism and clinical significance of PENK in patients with renal or cardiac failure. Proenkephalin (PENK), an endogenous opioid peptide present in the central nervous system and the autonomic nervous system in numerous organs including the heart, is implicated in ischemia preconditioning via the activation of delta-opioid receptors in heart tissue. This opens mitochondrial potassium-ATP channels, which are prevalent in heart mitochondria and prevent cytosolic calcium excess. As a result, the myocardial contractility, blood pressure, and heart rate are lowered . EnkephaThe effects of enkephalins on renal blood flow and urine output might cause the production of PENK as a counterregulatory response to renal failure. Without affecting the heart rate or blood pressure, activating enkephalin receptors causes diuretic and natriuretic responses ,20. AltePENK has also been utilized as a predictive marker in a variety of disorders, including acute myocardial infarction, sepsis, acute ischemic stroke, and diabetes. Nonetheless, its usefulness as a prognostic marker in heart failure patients remains inconclusive. A new investigation stated that the PENK level in acute HF patients might represent their heart and kidney condition; however, after adjustment for other renal biomarkers, including serum creatinine, the link was no longer independent. The statistical outcomes in the recent study supported the conclusion that the baseline plasma PENK and baseline serum creatinine had a high correlation; additionally, a linear association between the plasma PENK and plasma NGAL was demonstrated . The prognostic value of plasma PENK for type 1 cardiorenal syndrome (CRS-1) was explored in a study by Zhao et al. Patients with acute decompensated heart failure (ADHF) frequently experience CRS-1, which is described as a fast deterioration of cardiac function followed by acute kidney injury (AKI). The study found that, in hospitalized patients with ADHF, plasma PENK was a strong independent predictor for CRS-1. Furthermore, as plasma PENK increased, the prevalence of CRS-1 increased considerably. Again, in ADHF patients, the plasma PENK was an independent risk factor for HF readmission and all-cause mortality 90 days after discharge .Several indicators have sparked increased interest in the diagnosis, therapeutics, and prognosis of heart failure patients in recent years. Natriuretic peptides (NPs)—notably, B-type natriuretic peptide (BNP) and the N-terminal portion of its prohormone (NT-proBNP)—are the most widely acknowledged biomarkers for heart failure patients. Because of their high negative predictive value, NPs are commonly used as initial diagnostic tests to rule out the diagnosis of HF. Furthermore, in heart failure patients, NPs may lead to the decision to further explore cardiac conditions or predict the prognosis . NeverthPlasma PENK was measured by the chemiluminometric sandwich immunoassay technique, which researchers and clinicians have widely used in recent years. Two particular monoclonal antibodies directed against PENK 129–144 (anti-PENK 129–144 mAb) and PENK 152–159 (anti-PENK 152–159 mAb) are used in the measurement of plasma PENK. Samples (50 microliters plasma) were immobilized by the capture antibody (2 micrograms coated on polystyrene tubes). The detector antibody was labeled with methylacridinium ester, and bound chemiluminescence was measured. The results were contrasted with the predicted and observed concentrations of PENK. According to previous research findings, the assay technique successfully measured PENK in human specimens, defined as measuring within 15% of predicted quantities. The outcomes demonstrated a substantial correlation between the assay’s measurement of plasma PENK levels and GFR. Age, sex, and transplant status were significant predictors of GFR in a multivariate model, and 49% of the projected GFR values fell within 30% of the GFR .Emmens et al.  discoverNumerous studies on the connection between the kidney and the heart ,29 have Additionally, it is speculated that the drug used to treat heart failure may impact the body’s level of circulating PENK—specifically, the angiotensin receptor blocker/neprilysin inhibitors (ARNi), sacubitril, and valsartan. This effect may assist in explaining why ARNi can influence the PENK level, as enkephalins are a substrate of neprilysin  and can However, a contradictory study showed the correlation of PENK and the pro-BNP level at a 2-year follow-up following the start of ARNi treatment. Thus, the PENK level is still related to the disease progression .Our study identified a connection between plasma proenkephalin levels and numerous outcomes in heart failure patients, including all-cause death, rehospitalization, and decreasing renal function. These encouraging findings may pave the way for additional research into this biomarker. Furthermore, the findings of this study may encourage the use of proenkephalin as a predictive marker in patients with heart failure in current clinical practices.There are several limitations in this study. First, the number of studies is limited; as a result, additional research may be required to strengthen the findings. Second, because this is a meta-analysis of observational research, this study can only show relationships between plasma PENK levels and prognosis in heart failure patients, not a causative relationship. Next, in our meta-analysis, there was statistically significant heterogeneity between trials. This could be because of the patient’s gender, age, underlying condition, current medications, and other laboratory results. Furthermore, because the cut-off values in the studies differ, the precise definition of a high plasma PENK level remains unknown. As a result, future research should clearly define the high plasma PENK level threshold. Moreover, existing studies have primarily focused on American and European patients; thus, research on other ethnic groups should be encouraged because plasma PENK levels may change between ethnic groups. Finally, one of the significant limitations that is worth mentioning is the heterogeneity in the enrolled studied population. It also does not distinguish between patients with preserved ejection fraction and those with decreased ejection fraction, which may influence the outcome because of the different pathophysiology, as preserved ejection fraction heart failure may not involve worsening cardiac function, as in high output failure. Most of the included studies combined both subtypes during enrollment. Therefore, a separate analysis between HFrEF and HFpEF was not possible. More research on specific types of patients is thus recommended.Our study demonstrated associations of the plasma PENK level and HF prognoses, which are all-cause mortality, rehospitalization, and worsening renal function. These findings could suggest that the opioid system is implicated in the worsening of cardiovascular functioning in heart failure. We encourage additional research into this biomarker element and look forward to the outcomes of prospective randomized trials investigating this issue. PENK level-guided therapy may be a viable option for routine heart failure treatment.


Eight atrioventricular points were defined at end diastole and end systole in 2-, 3- and 4-chamber cine long-axis views for computation of AVPD and longitudinal contribution to stroke volume (SVlong%). Cut-off values for survival analysis were defined as two standard deviations above or below the mean of the controls. Outcome was defined as death or lung transplantation. Median follow-up time was 3.6 [IQR 3.7] years. Patients were 57 ± 19 years (65% women) and controls 58 ± 15 years (70% women). Biventricular AVPD, SVlong% and ejection fraction (EF) were lower and SVlat% was higher, while SVsept% was lower in PAH compared with controls. In PAH, transplantation-free survival was lower below cut-off for LV-AVPD  and RV-AVPD . In Cox regression analysis, lower LV-AVPD and RV-AVPD inferred lower transplantation-free survival . LV-SVlong%, RV-SVlong%, LV-SVlat%, RV-SVlat%, SVsept% and LV- and RVEF did not affect outcome. Low left and right AVPD were associated with outcome in PAH, but regional contributions to stroke volume and EF were not.To investigate if left and right atrioventricular plane displacement (AVPD) or regional contributions to SV are prognostic for outcome in patients with pulmonary arterial hypertension (PAH). Seventy-one patients with PAH and 20 sex- and age-matched healthy controls underwent CMR. Myocardial borders and RV insertion points were defined at end diastole and end systole in cine short-axis stacks to compute biventricular volumes, lateral (SV Pulmonary arterial hypertension (PAH) is a rare disease with high morbidity and mortality rates when right heart failure is developed , 2.Cardiac magnetic resonance imaging (CMR) is the gold standard for assessment of ventricular volumes and global function, especially on the right side of the heart . CurrentOne proposed metric is the regional deformation of the heart during contraction, and it has earlier been shown that RV longitudinal strain is prognostic in PAH . While slong%) can be quantified from AVPD and the radial component can be calculated from the septal contribution to SV (SVsept%) and lateral contribution to SV (SVlat%) measured by CMR  were used. Standard cine balanced steady-state free precession images of three long-axis views and a short-axis stack covering the entire heart were acquired in supine position with a cardiac coil, using electrocardiography triggering during end-respiratory breath-hold. Typical image parameters for Siemens were: Temporal resolution of 46 ms reconstructed to 25 time phases per cardiac cycle, 60° flip angle, 3-ms repetition time, 1.4-ms echo time, and slice thickness 6 mm with 2-mm slice gap; and for Philips: Temporal resolution of 47 ms reconstructed to 30 time phases per cardiac cycle, 60° flip angle, 3-ms repetition time, 1.4-ms echo time and slice thickness 8 mm with no slice gap. Typical in-plane resolution was 1.5 × 1.5 mm. Late gadolinium enhancement images were acquired 15–20 min after gadolinium-based contrast agent  injection in the corresponding short- and long-axis view as for the standard cine balanced steady-state free precession images. All images were obtained in supine position at end-expiratory breath-hold. Typical image parameters: 8 mm slice thickness (no gap) with in-plane resolution 1.5 × 1.5 mm and prospective electrocardiography gating. Inversion time was chosen to null remote myocardium .http://segment.heiberg.se)  according to normal distribution. Normal distribution was assessed using Shapiro–Wilk tests. Categorical variables were expressed as absolute numbers and proportion (in percentage). Group comparisons for parametric data were analyzed with independent samples T-tests, and Mann–Whitney U-test for non-parametric data. Two-sided Chi-square was used for nominal data. Values were predefined as being altered when more than 2SD from the mean of the control group and being within limits of normal distribution when within 2SD. Kaplan–Meier plots were used for survival curves with Cox regression analysis for calculating hazard ratio (HR) and log-rank test for p-values. Cox regression analysis was performed as univariate analysis for continuous variables. In the bivariate analysis, variables with p < 0.1 from the univariate analysis were included. A two-sided p-value < 0.05 was considered statistically significant.Statistical analysis was performed in IBM SPSS Statistics for Windows, Version 25.0  and GraphPad Prism version 7.00 for Windows  were included  and late gadolinium enhancement was present in 56 patients (93%). Of those, late gadolinium enhancement was present at the RV insertion points in all 56 patients, in the septum in two patients, in the lateral LV wall in five patients and in the RV in one patient. There was no significant difference in patients without events compared to patients with events with regards to late gadolinium enhancement (p = 0.5). There was no difference in LV-AVPD or RV-AVPD between patients with late gadolinium enhancement compared to patients without .There were 42 events, of which 36 were deaths and 6 lung transplantations Table . Patientlong%: < 41.4%, RVSVlong%: < 63.8%, SVsept%: < 0.8%, LVEF: < 53% and RVEF: < 48% as well as LVSVlat%: > 46.9% and RVSVlat%: > 44.5%. The mean and SD values are presented in Tables The cut-off values for survival analysis were, for LV-AVPD: < 12.0 mm, RV-AVPD: < 16.8 mm, LVSVlong%, RV-SVlong%, SVsept%, LVEF or RVEF or high values of LV-SVlat% or RV-SVlat% did not have a different outcome compared with patients with values within limits  in PAH that found a HR of mortality being 1.72 per 5 mm decrease in TAPSE (p < 0.001) [We found that each mm decrease in LV-AVPD and RV-AVPD was associated with decreased transplantation-free survival of 16% and 11%, respectively. Although there is a lack of previous studies analyzing AVPD, the findings for RV-AVPD is in line with the earlier meta-analysis by Baggen et al< 0.001) .. showing that TAPSE ≤ 15 mm predicted higher mortality with a HR of 3.5 compared with TAPSE > 15 mm [When applying Kaplan Meier analysis with dichotomized cut-off values below 2SD from the means of the healthy controls, we found HR > 2 for lung transplantation or death when LV-AVPD was < 12.0 mm and HR ~ 10 when RV-AVPD was < 16.8 mm. The low transplantation-free survival occurring with low RV-AVPD is in line with an echocardiographic study by Schuuring et al > 15 mm .. found no significant differences in mortality in patients with low TAPSE ≤ 14 mm compared with TAPSE > 14 mm [. the cut-off was computed from normal values while in the study by Cho et al. infra- and supra-median values were used as cut-offs [. than with Cho et al.[However, TAPSE with echocardiography has shown conflicting results, as a study by Cho et al > 14 mm . In the cut-offs , 21. As ho et al., 21.It should be noted that although both AVPD and TAPSE measure the movement of the tricuspid annulus, the methods are different. TAPSE measures the movement of the lateral tricuspid annulus towards the apex and AVPD the movement of the entire atrioventricular plane towards the apex. This difference results in a lower AVPD value compared with TAPSE, as the highest AVPD movement often is found in the lateral tricuspid annulus and the mean AVPD includes the septal and RV outflow tract parts of AVPD. Furthermore, echocardiography and CMR AVPD-based values seem to be interchangeable in a healthy adult population , but lesA novel finding in the present study was low LV-AVPD being predictive of reduced survival. The implications of reduced LV-AVPD on outcome have not been shown previously. The cause of the failing LV could be a result of underfilling of the LV or interventricular interdependence of the heart . Thus, wIt should be noted that while LV-AVPD had a higher hazard ratio compared with RV-AVPD using continuous variables, RV-AVPD had a higher hazard ratio using dichotomized variables from normal values. This might suggest that the association with decreased survival due to low RV-AVPD might be more threshold dependent while the association with LV-AVPD is of a more continuous nature.Another method of evaluating longitudinal function is cardiac deformation using longitudinal strain. It has been shown that reduced RV longitudinal strain is associated with increased risk for death, lung transplantation and functional class deterioration in pulmonary hypertension . In addilong%, RV-SVlong%, LV-SVlat%, RV-SVlat% or SVsept% and outcome. It might seem counterintuitive that there were correlations between low AVPD in both ventricles and decreased survival but not between low SVlong% and survival. However, low AVPD does not directly imply low SVlong%, since SVlong% depends on both AVPD and the area in the short axis. So, even if AVPD decreases, SVlong% can be preserved or even increased if the short-axis area increases. A similar effect has been observed in patients with left heart failure with dilated LV and low SV, where LV-SVlong% can be preserved even with low LV-AVPD owing to larger LV basal area [There were no associations between LV-SVsal area .. confirmed that RVEF was a strong predictor of all-cause death in pulmonary hypertension of several etiologies, but in patients with PAH without congenital heart disease, RVEF was, in fact, not a predictor of outcome [Neither RVEF nor LVEF were associated with decreased survival among patients with PAH in the present study. Previous studies on RVEF and survival in PAH show conflicting results –29. One  outcome , 5. Furt outcome , 29. Reg outcome , and ourLikewise, although patients in the present study had lower SV, lower LV end-diastolic volume and higher RV end-diastolic volume compared to controls, there was no association between these three variables and survival. This is in contrast with a previous study where the same variables predicted a worse prognosis . HoweverIn the present study, the proportion of prevalent patients were higher in the group having events and in cox regression prevalent patients had worse prognosis when adjusted for age. This is in contrast to a study with 674 patients with idiopathic, familial and anorexigen-associated PAH, in which incident patients had worse prognosis than prevalent . Howeverlong% and high SVlat% in both ventricles as well as a low SVsept% compared with healthy controls. This indicates an alteration in regional cardiac pumping with decreased longitudinal pumping and increased radial pumping, in both ventricles in patients with PAH.In the present study, patients with PAH had low AVPD, SVIn the present study, patients with PAH had longitudinal and lateral contributions to SV in the RV, similar to what is normally seen in the LV . It has On the other hand, the decrease in longitudinal pumping and increase in radial pumping of the LV is less intuitive. We suggest that the changes in LV function could be due to diastolic and systolic ventricular interdependence of the heart or underfilling of the LV due to inadequate RV forward pumping , 37. Thisept% in patients compared with controls. This might be a sign of increased paradoxical septal motion, which has previously been described in patients with pressure-loaded RV and has been associated with poor outcome in precapillary pulmonary hypertension [In PAH, the morphology of the septum changes as an effect of a change in the pressure gradient between the LV and the RV, and as the pressures equalize the septum flattens . In the rtension .The study is retrospective and hence there is a risk of selection bias. However, as all patients were referred from a tertiary PAH center, where a standardized clinical routine include CMR assessment, there is a low likelihood for substantial referral bias. In addition, risks for selection bias have been minimized by screening all patients that underwent CMR during the selected time period for study participation.In our population, both newly diagnosed and prevalent patients were included. However, we intended to investigate if AVPD and regional contribution was indicative of outcome in any patient with PAH irrespective of stage of disease progress.Some of the comparisons, mainly RVEF and RV-AVPD, had large differences in group sizes. This was due to the method of using cut-off values from healthy controls ± 2SD for Kaplan–Meier analysis. However, the Kaplan–Meier analyses were largely in agreement with the Cox regression analysis.The proportion of women was higher among patients without events than patients with events. It has been suggested that men have worse prognosis compared with women with PAH, although this might be owing to lower RVEF rather than sex-differences in itself . HoweverLow left and right AVPD were both associated with outcome in PAH, but regional contributions to stroke volume and EF were not. This implies that AVPD measured with CMR could be a useful tool in assessing the disease progress and risk assessment in PAH.