The objective of this study was to evaluate the mechanical and histological properties of a fully absorbable poly-4-hydroxybutyrate/absorbable barrier composite mesh (Phasix™ ST) compared to partially absorbable , fully absorbable (Phasix™), and biologically derived (Strattice™) meshes in a porcine model of ventral hernia repair.n = 6 mesh/group/time point).Bilateral abdominal surgical defects were created in twenty-four Yucatan pigs, repaired with intraperitoneal  or retromuscular  mesh, and evaluated at 12 and 24 weeks (p < 0.001) strength (636.6 ± 192.1 N) compared to Ventralight™ ST (324.3 ± 37.1 N), Phasix™ ST (206.9 ± 11.3 N), and Phasix™ (200.6 ± 25.2 N). At 12 and 24 weeks, mesh/repair strength was significantly greater than NAW , and no significant changes in strength were observed for any meshes between 12 and 24 weeks (p > 0.05). Phasix™ mesh/repair strength was significantly greater than Strattice™ (p < 0.001) at 12 and 24 weeks, and Ventralight™ ST mesh/repair strength was significantly greater than Phasix™ ST mesh (p < 0.05) at 24 weeks. At 12 and 24 weeks, Phasix™ ST and Ventralight™ ST were associated with mild inflammation and minimal–mild fibrosis/neovascularization, with no significant differences between groups. At both time points, Phasix™ was associated with minimal–mild inflammation/fibrosis and mild neovascularization. Strattice™ was associated with minimal inflammation/fibrosis, with minimal neovascularization at 12 weeks, which increased to mild by 24 weeks. Strattice™ exhibited significantly less neovascularization than Phasix™ at 12 weeks and significantly greater inflammation at 24 weeks due to remodeling.Prior to implantation, Strattice™ demonstrated significantly higher  and fully resorbable (Phasix™) meshes at 12 and 24 weeks in this model. Data also suggest that fully absorbable meshes with longer-term resorption profiles may provide improved mechanical and histological properties compared to biologically derived scaffolds. If we could artificially produce tissues of the density and toughness of fascia and tendon the secret of the radical cure of hernia would be discovered.” . Animals were placed in dorsal recumbent position, and the abdomen was shaved and prepared for aseptic surgery using accepted veterinary care standards.The animals were not offered their daily food ration prior to surgical induction, but water was not restricted. On the morning of surgery, Rimadyl® ]. Animals were survived for 12 or 24 weeks  and then sedated with Telazol® , anesthetized with isoflurane, and euthanized via an overdose of potassium chloride solution, IV.A 30-cm midline incision was created, and a midline laparotomy performed to open the peritoneal space. Two lateral 1-inch (2.54 cm) surgical defects were created, one on each side of the midline, using a circular die-cutting tool. The tool was rotated to create a full-thickness muscular defect through the lateral and transverse oblique muscles. The muscle at the defect site was then reapproximated with 2-0 PDS™ suture, and the peritoneum was closed over the repaired muscular defect using 2-0 PDS™ suture. Phasix™ ST and Ventralight™ ST meshes were die-cut into 3.25-inch (8.26 cm)-diameter circles and hydrated in sterile saline for 1–3 s. Meshes were then fixated to the peritoneum over the defect site using 12–14 SorbaFix™ fasteners around the periphery of the mesh. A single mesh type was implanted in a given animal. The abdomen was closed using standard closure techniques. Bupivacaine was infused into the midline incision site (not exceeding 2 mg/kg). Analgesics were administered for the first 72 postoperative hours and continued on an as-needed basis thereafter [buprenorphine (0.02 mg/kg) and RimadylAnimals with meshes implanted in the retromuscular plane underwent an identical surgical protocol as those with meshes placed intraperitoneally, except that the peritoneum was left intact in these animals and was therefore not incised or repaired. Briefly, two lateral 1-inch (2.54 cm) surgical defects were created, one on each side of the midline, using a circular die-cutting tool. The tool was rotated to create a full-thickness muscular defect through the lateral and transverse oblique muscles. The muscle at the defect site was then reapproximated with 2-0 PDS™ suture, and Phasix™ or Strattice™ was implanted in the retromuscular plane and fixated circumferentially with 12 SorbaFix™ fasteners (for Phasix™) or 12 Nurolon™ sutures (for Strattice™), respectively.®, MTS) with a 2kN load cell and a data acquisition rate of 10 Hz. Non-implanted meshes were hydrated and evaluated to establish the baseline (T0) ball burst strength of each mesh type . Specimens of corresponding NAW (without mesh or hernia defect) were also obtained immediately lateral to the defects and mechanically evaluated to establish the baseline characteristics of the porcine abdominal wall in the absence of a hernia defect or mesh repair (n = 6 for each time point/mesh group). The entire mesh/repair site (3.25 inch diameter) was evaluated for the explanted meshes (n = 6 for each time point/mesh group). All Nurolon™ sutures and SorbaFix™ fixation devices were left intact within the mesh/repair site, and the entire specimen including fixation devices was clamped within the test fixture. All mechanical evaluations were conducted on explanted specimens that were clamped inbound of fixation points, thereby eliminating the impact of fixation on mechanical testing. Specimens measured 3.25 inches in diameter and were mounted in a test fixture between two polymer plates measuring 12 × 16 inches each and coated with 120-grit sandpaper to maximize grip and prevent slippage of the tissue. The upper plate had an aperture of 0.43 inch diameter to accommodate passage of the 0.37-inch-diameter probe and an aperture of 0.87 inch diameter in the lower plate to avoid unnecessary stress on the tissue as it was displaced by the probe. The 0.37-inch-diameter probe was centered directly over the defect site in each specimen and applied in compression at a rate of 1 inch/min until it burst through. The peak load was recorded as the ball burst strength (N). The NAW strength was calculated as the average of specimens obtained from animals in the 12- and 24-week groups combined.Following euthanasia, as shown in Fig. Following mechanical testing, the 3.25-inch-diameter mesh/repair specimen was cut in half, lengthwise through the defect, and half of the specimen was placed in 10 % neutral buffered formalin for histological analysis. The specimens were then processed, embedded, sectioned at ~5 µm, and stained with hematoxylin & eosin (H&E) and Masson’s trichrome (MT). Slides were prepared from areas lateral to the repair rather than centered over the defect area of the specimen. Histological evaluation was conducted by an independent, board-certified veterinary pathologist at CBSET, Inc. . The host tissue response was assessed via microscopic evaluation of H&E-/MT-stained slides. The host inflammatory/fibrotic response and neovascularization were scored for one section of each slide according to an established semiquantitative scale: 0 = no response; 1 = minimal/barely detectable; 2 = mild/slightly detectable; 3 = moderate/easily detectable; and 4 = marked/very evident –25.0) were compared via a one-way analysis of variance (ANOVA), followed by Tukey’s multiple comparison post test. A one-way ANOVA was also performed on the postimplantation ball burst data, followed by Bonferroni’s multiple comparison post test. Data are presented as mean ± standard deviation. A nonparametric Kruskal–Wallis analysis was performed on the histology data , followed by Dunn’s multiple comparison post test. Data are presented as median with interquartile range (25-75 %). The threshold of statistical significance was set at p < 0.05. Meshes implanted in the intraperitoneal and retromuscular planes were analyzed separately.Data were collected, analyzed, interpreted, and graphically displayed using GraphPad Prism 6.01 statistical software. Baseline mesh strength values (T0) of Strattice™ (636.6 ± 192.1 N) was significantly greater than the hydrated preimplantation strength of Ventralight™ ST (324.3 ± 37.1 N), Phasix™ ST (206.9 ± 11.3 N), and Phasix™ (200.6 ± 25.2 N) .As shown in Fig. 0 strength of the mesh alone. Furthermore, the Phasix™ ST mesh/repair strength at 24 weeks (275.8 ± 59.6 N) was 33 % greater than the T0 strength of the mesh alone. However, it should be noted that this increase in strength relative to the T0 strength of the mesh alone represents the contribution of the abdominal wall, any newly formed tissue, and the mesh scaffold. No significant change in mesh/repair strength was observed for Phasix™ ST between 12 and 24 weeks . The mesh/repair strength of Phasix™ ST was also significantly greater than the NAW (61.5 ± 16.7 N) at both 12 and 24 weeks (p < 0.001 in both cases).As shown in Fig. 0 strength of Ventralight™ ST alone. Additionally, no significant change in mesh/repair strength was observed for Ventralight™ ST between 12 and 24 weeks . However, the mesh/repair strength of Ventralight™ ST was significantly greater than the NAW (76.0 ± 27.6 N) at both 12 and 24 weeks (p < 0.001 in both cases).In contrast, Fig. p > 0.05). However, the mesh/repair strength of Ventralight™ ST (336.4 ± 42.1 N) was significantly greater than Phasix™ ST (275.8 ± 59.6 N) at 24 weeks (p < 0.05).As shown in Fig. 0 strength of the mesh alone. Furthermore, the Phasix™ mesh/repair strength at 24 weeks (317.1 ± 85.6 N) was 58 % greater than the T0 strength of the mesh alone. Again, it is important to note that this increase in strength relative to the T0 strength of the mesh alone represents the contribution of the abdominal wall, any newly formed tissue, and the mesh scaffold. No significant change in mesh/repair strength was observed for Phasix™ between 12 and 24 weeks . However, mesh/repair strength of Phasix™ was significantly greater than the NAW (78.4 ± 25.0 N) at 12 and 24 weeks (p < 0.001 in both cases).As shown in Fig. 0 strength of the mesh alone. However, no significant change in mesh/repair strength was observed for Strattice™ between 12 and 24 weeks . The mesh/repair strength of Strattice™ was significantly greater than the NAW (51.9 ± 20.2 N) at 12 and 24 weeks .In contrast, Fig. p < 0.001). Similarly, the mesh/repair strength of Phasix™ (317.1 ± 85.6 N) was significantly greater than Strattice™ (173.6 ± 51.1 N) at 24 weeks (p < 0.001).As shown in Fig. Although Phasix™ ST versus Strattice™ and Phasix™ versus Ventralight™ ST were not directly compared in the statistical analyses due to implantation in different tissue planes , some interesting observations were made when reviewing the data for all meshes without regard to tissue plane. At 12 weeks, Ventralight™ ST (331.9 ± 20.2 N), Phasix™ ST (298.4 ± 24.7 N), and Phasix™ (271.4 ± 52.7 N) all displayed similar mesh/repair strength, which were approximately twice the strength exhibited by Strattice™ (140.4 ± 37.3 N). This trend continued at 24 weeks, with Ventralight™ ST ™ (336.4 ± 42.1 N), Phasix™ ST (275.8 ± 59.6 N), and Phasix™ (317.1 ± 85.6 N) all displaying similar mesh/repair strength, which remained approximately 1.5–2 times the strength of Strattice™ (173.6 ± 51.1 N), respectively.Figure p > 0.05 in all cases). Similarly, Ventralight™ ST was associated with mild inflammation (median = 2.0), minimal to mild fibrosis (median = 1.5), and mild neovascularization (median = 2.0), which did not change significantly between 12 and 24 weeks . No significant differences were observed between the inflammation, fibrosis, or neovascularization scores associated with Phasix™ ST and Ventralight™ ST at either 12 or 24 weeks . At both time points, the absorbable hydrogel barrier and PGA fibers of Phasix™ ST and Ventralight™ ST were completely resorbed, whereas the primary mesh components of these devices  remained intact.As shown in Table p > 0.05 in all cases). Similarly, Strattice™ was associated with minimal inflammation and fibrosis (median = 0.5–1.0) that did not change significantly between 12 and 24 weeks . However, Strattice™ was associated with minimal neovascularization at 12 weeks (median = 1.0 and interquartile range = 0.0–1.25) that significantly increased to mild neovascularization at 24 weeks . Furthermore, Strattice™ exhibited significantly less neovascularization at 12 weeks compared to Phasix™  and significantly less inflammation at 24 weeks with evident resorption/remodeling of this scaffold compared to Phasix™ . By 24 weeks, the primary mesh component of Phasix™ (P4HB) remained intact, whereas Strattice™ demonstrated evident resorption/remodeling at this time point.As shown in Table The objective of this study was to evaluate the mechanical and histological properties of a fully absorbable poly-4-hydroxybutyrate/absorbable barrier composite mesh (Phasix™ ST) compared to partially absorbable , fully absorbable (Phasix™), and biologically derived (Strattice™) meshes in a porcine model of ventral hernia repair.Mechanical testing revealed that sites repaired with coated (Phasix™ ST) or uncoated (Phasix™) versions of the poly-4-hydroxybutyrate technology had similar mesh/repair strength and were both significantly stronger than NAW at 12 and 24 weeks. These results suggest that Phasix™ ST and Phasix™, with associated tissue ingrowth, augmented the strength of the NAW despite partial resorption of mesh fibers comprising these devices. In addition, Phasix™ ST and Phasix™ demonstrated comparable mesh/repair strength to Ventralight™ ST, which suggests that they may provide medium-term mechanical strength comparable to partially absorbable mesh incorporating a permanent polypropylene scaffold. However, it is noteworthy that Ventralight™ ST exhibited significantly greater mesh/repair strength at 24 weeks compared to Phasix™ ST, which may be due to volume differences in PGA fiber content (Phasix™ ST possesses ~40 % less PGA fiber), biomechanical differences between P4HB/polypropylene load-bearing components, and/or partial resorption of P4HB.Although exhibiting the greatest preimplantation strength of all biomaterials evaluated in this study, biologically derived (Strattice™) mesh/repairs demonstrated 78 % lower mechanical strength relative to preimplantation strength at 12 weeks, indicating a rapid strength decline in vivo. Comparatively, sites repaired with Strattice™ were significantly weaker than sites repaired with the fully absorbable biosynthetic mesh (Phasix™), as early as 12 weeks. These biologically derived scaffold observations are similar to previously reported results by Cavallo et al. that demonstrated 91 % and 96 % lower mechanical strength for biologically derived (Strattice™) mesh/repairs relative to preimplantation strength at 1 and 6 months, respectively , 26. Sim® Bio-A®) in CDC class II to III patients [As demonstrated through mechanical testing in this porcine study, the relatively slow degradation rate of the load-bearing component within Phasix™ ST and Phasix™ (P4HB) may be advantageous in facilitating a more gradual transfer of load from the mesh back to the native tissue compared to biologically derived or rapidly resorbing synthetic biomaterials. Rapid mechanical degradation of biomaterials could result in premature transfer of load back to the native tissue before the repair site has been fully remodeled and strengthened by mature collagen and may ultimately contribute to hernia recurrence rates. Within the Repair of Infected or Contaminated Hernias (RICH) clinical trial (NCT00617357), Itani et al. previously reported 28 % hernia recurrence at 2 years following ventral hernia repair with biologically derived non-cross-linked porcine dermis (Strattice™) in CDC class II to IV patients [patients . AdditioThe predictable, long-term resorption profile associated with Phasix™ ST and Phasix™ may also be beneficial in protecting these meshes from rapid degradation by collagenases if inadvertently exposed to bacteria during/after implantation. Deeken et al. have shown that Strattice™ is rapidly degraded by collagenases during in vitro studies, leading to a significant loss of mechanical strength, particularly when compared to cross-linked porcine dermis material such as Permacol™ . AdditioHistological analysis of each mesh was performed to provide additional insight into the host response associated with each of the mesh materials evaluated in this study. The results revealed that Phasix™ ST mesh exhibited minimal–mild inflammation, fibrosis, and neovascularization characteristics comparable to Ventralight™ ST and Phasix™. Additionally, these three meshes exhibited similar responses at both 12 and 24 weeks, indicating a stable host tissue response with insignificant changes over time.In contrast, Strattice™ was associated with significant changes in neovascularization over time. At 12 weeks, neovascularization scores for Strattice™ were significantly lower than scores reported for Phasix™ mesh. However, neovascularization scores for Strattice™ increased significantly between 12 and 24 weeks, reaching levels of neovascularization comparable to the other three mesh types by 24 weeks. Morphological characteristics such as overall surface area may contribute to these temporal differences between materials. The microporous, sheet-like structure inherent in biologically derived scaffolds may slow the overall rate of tissue integration and vascularization compared to the macroporous, monofilament structure of Phasix™ ST and Phasix™, which facilitates rapid integration and neovascularization, similar to traditional and composite ventral hernia repair prosthetics.Interestingly, Strattice™ was also associated with significantly less inflammation at 24 weeks compared to Phasix™ mesh. This may be explained by the differing resorption profiles associated with these materials. As shown in Fig. The results of this study compare well with similar, previously published studies , 27, 32.0 and NAW specimens chosen for this study. In future studies, it may be useful to also include a T0 sample of mesh/tissue repair strength immediately after surgical implantation of the mesh over a repaired defect in addition to the T0 mesh-only data acquired here. This type of specimen would provide additional insight into the contribution of the repaired tissue to the strength of the initial mesh/tissue repair prior to mesh resorption or tissue ingrowth. Finally, it should be acknowledged that specimens obtained for histological analysis were taken after the completion of mechanical testing. It is possible that artifacts were created in the tissue specimens due to compression during testing, although no such observations were noted by the pathologist.There are some limitations associated with the current study that deserve consideration. First, the medium-term implant duration of 24 weeks is limited given the longer-term resorption profile associated with Phasix™ ST and Phasix™ compared to that associated with Strattice™. The results of this study provide an understanding of the short- to medium-term tissue response and mechanical properties associated with these materials. However, future studies should include longer implant durations to more fully characterize the responses associated with these materials after complete resorption of not only the barrier layer, but also the primary load-bearing structural component of the mesh. Additionally, although this study provides important insight using an established large animal model, the impact of mesh resorption on hernia recurrence rates and clinical performance should be addressed in future clinical trials. Furthermore, there are some limitations associated with the TPhasix™ ST demonstrated comparable mechanical and histological properties to partially absorbable  and fully resorbable (Phasix™) meshes at 12 and 24 weeks in a porcine model of ventral hernia repair. Data also suggest that longer-term, fully absorbable mesh devices may provide more optimal mechanical and histological properties to support gradual load transfer to the abdominal wall than biologically derived scaffolds for soft tissue repair/reconstruction within this porcine model.


With the advent of magnetic resonance imaging (MRI) conditional pacemaker systems, the possibility of performing MRI in pacemaker patients has been introduced. Besides for the detailed evaluation of atrial and ventricular volumes and function, MRI can be used in combination with body surface potential mapping (BSPM) in a non-invasive inverse potential mapping (IPM) strategy. In non-invasive IPM, epicardial potentials are reconstructed from recorded body surface potentials (BSP). In order to investigate whether an IPM method with a limited number of electrodes could be used for the purpose of non-invasive focus localization, it was applied in patients with implanted pacing devices. Ventricular paced beats were used to simulate ventricular ectopic foci.Ten patients with an MRI-conditional pacemaker system and a structurally normal heart were studied. Patient-specific 3D thorax volume models were reconstructed from the MRI images. BSP were recorded during ventricular pacing. Epicardial potentials were inversely calculated from the BSP. The site of epicardial breakthrough was compared to the position of the ventricular lead tip on MRI and the distance between these points was determined.For all patients, the site of earliest epicardial depolarization could be identified. When the tip of the pacing lead was implanted in vicinity to the epicardium, i.e. right ventricular (RV) apex or RV outflow tract, the distance between lead tip position and epicardial breakthrough was 6.0 ± 1.9 mm.In conclusion, the combined MRI and IPM method is clinically applicable and can identify sites of earliest depolarization with a clinically useful accuracy.The online version of this article (doi:10.1007/s10840-015-0054-9) contains supplementary material, which is available to authorized users. Invasive electrophysiological procedures are often complicated by considerable fluoroscopic time, non-inducibility of the arrhythmia or hemodynamic instability of the patient . Therefoin vivo studies with respect to the accuracy and validity of the estimated epicardial potentials or intramural activation times.To this intent, over the last decade various non-invasive mapping strategies, e.g. electrocardiographic imaging (ECGI) , non-invWith the advent of magnetic resonance imaging (MRI) conditional pacemaker systems, the possibility of performing MRI in pacemaker patients has been introduced . BesidesThis pilot study investigated the feasibility of non-invasive focus localization using a limited number of 62 electrodes in patients with an implanted MRI-conditional pacemaker system. Ventricular paced beats were used to simulate ectopic foci. The estimated site of earliest epicardial breakthrough was compared to the position of the ventricular lead tip, and the distance between these sites was determined.Inverse potential mapping was performed in ten male patients (mean age 64 ± 5 years old) with an implanted MRI-conditional DDD pacemaker system  and a structurally normal heart. Patient characteristics are provided in Table The study complied with the declaration of Helsinki and received approval from the local ethical committee and the institutional scientific board. Written informed consent was obtained from all patients.An overview of the complete workflow is provided in Fig. Body surface potentials (BSP) were recorded using a 65-channel (62 torso + 3 limb electrodes) ActiveTwo BSPM system with passive electrodes and shielded cables . The BSP electrodes were positioned on the anterior thorax using a 20-mm inter-electrode distance Fig.  7]. BSP. BSP7]. After BSPM, MRI markers were applied to replace all torso electrodes. These markers were used to locate the electrode positions on the MRI images, thereby minimizing the systematic error in the inverse procedure. Before entering the MRI room, pacing thresholds, P- and R-wave amplitude, and lead impedance were determined and the pacemaker system was programmed into MRI SureScan® mode .In order to control lung volume, breath holding was practiced with the patient prior to the examination. A stack of ECG-triggered, T2-weighted, bright blood images  was acquired to record the anatomy of the thorax and register the position of the RV lead tip and torso electrodes. Subsequently, cardiac function was assessed using steady state free precession (SSFP) short-axis, three- and four-chamber cines . All images were obtained during breath-hold on a Siemens Aera 1.5 Tesla MRI scanner . Cardiac function was analysed using CMR42® software .After the examination, pacing thresholds, P- and R-wave amplitude and lead impedance were determined and compared to the initial values. Finally, original programming of the pacemaker was restored.For every patient, a detailed anatomical thorax model, including a 3D whole-heart model, was constructed from the MRI images. Thoracic structures including the heart with all four compartments, lungs, liver and spleen were manually segmented directly in 3D using custom-written software. Conductivities were assigned to each of these structures as known from literature  . A trianPepi) were calculated from the recorded body surface potentials (Pbs) using Pepi = (TTT + λ2I)−1TTPbs where T is the forward transfer matrix and λ is the regularization strength (0.01). Finally, an epicardial potential map of a single paced ventricular beat was reconstructed.For each patient, a single paced beat within the 10-s acquisition window was selected for inverse computation. The electrograms do not require any specific editing prior to processing. Epicardial potentials (An investigator (PB), blinded to the actual ventricular lead tip position, identified the site of earliest depolarization on the colour-coded epicardial potential map. Subsequently, the distance between this site and the position of the ventricular lead tip on the MRI images was determined.In order to evaluate the reproducibility of the applied IPM method, two different paced beats were analysed for each patient. The epicardial potential distribution was reconstructed independently. Subsequently, the correlation between the epicardial potentials estimated from the two different beats was calculated using custom-written software.Results are shown as mean ± SD and are expressed as absolute values. All analyses were performed on a 2.4-GHz quad core laptop running the Windows 8 OS. Solving the potential equations was delegated to an Ubuntu 12.10 virtual machine running on this laptop.The BSP recording and MRI examination lasted approximately 60 min. None of the patients reported any complaints during or after the MRI examination. Pacing thresholds and leads impedances remained unaffected by the MRI scan in all patients.Despite the presence of a pacemaker, image quality was good to excellent in all patients and allowed for left and right ventricular function assessment , depolarization started in the superior part of the right ventricular septum. A rapid subsequent depolarization of the right ventricular free wall was observed video .In two patients (patients 1 and 2), the site of earliest depolarization was located in the apical region of the right ventricle. From that point, depolarization spread rapidly to the basal portion of both the RV and left ventricle (LV) (video In patients with the tip of the pacing lead close to the epicardium (apex or right ventricular outflow tract), the distance between lead tip position and epicardial breakthrough was 6.0 ± 1.9 mm.For the patients with the tip of the pacing lead implanted in the middle of the mid-ventricular septum, the observed site of epicardial breakthrough varied substantially across the right ventricular free wall. In these patients, the intrinsic distance from the lead tip to the epicardium was relatively large . This distance contributes significantly to the measured localization error .r = 0.97–0.99, p < 0.001) between the epicardial potential distributions of two different paced beats was calculated  or in humans during conventional electrophysiological studies –14.In the past, a limited number of patients with an implanted pacemaker have been studied for validation purposes. In these studies, ECGI uses 254 torso electrodes and CT images to calculate epicardial potentials. In only one patient with an implanted cardiac resynchronization therapy (CRT) device, a localization error of 7 mm for the RV pacing lead and 11 mm for the LV lead has been reported .NICE uses 65 electrodes and MRI images to estimate endo- and epicardial activation times. NICE has been applied in ten patients with an implanted CRT device  and in oRecently, Revishili et al.  demonstrIn this study, all BSP electrodes were positioned in a matrix, directly overlaying the heart. By concentrating the electrodes, a localization error of 6.0 ± 1.9 mm was found for patients with the tip of the pacing lead close to the epicardium. The rapid positioning of this electrode array may facilitate the incorporation of this technique in clinical practice.Currently, only epicardial potentials can be reconstructed from the recorded BSP. Reconstruction of both epicardial and endocardial activation would require the application of an a priori activation model . Use of a priori models mandates various assumptions to be made and limits the number of pathology related activation patterns that can be represented.As described previously by Rudy and co-workers, epicardial potentials contain information on intramural and endocardial activation even before the epicardium is activated . EpicardIn patients with implanted pacing devices, visualization of epicardial activation may provide additional insight into the efficacy of the pacing strategy. Changes in depolarization or repolarization or other signs of adverse pacing effects may be detected at an early stage. Various studies have demonstrated that long-term ventricular pacing may have various unintended adverse electrophysiological and mechanical effects , 22. In Using MRI as a reference for the RV lead tip position is a novelty. The introduction of MRI-conditional pacemaker systems enables the use of MRI for IPM. Unlike CT, MRI is not associated with radiation exposure. MRI-conditional devices can be programmed in an MRI safe mode, which makes the device less susceptible to the magnetic energy of the MRI environment and decreases the risk of hard- or software interactions.Besides visualizing the lead position, MRI may provide valuable information on the mechanical activation in patients with implanted pacemaker systems. In contrast to CT, MRI enables the safe performance of follow-up studies. In addition, MRI is the gold standard for the detailed assessment of atrial and ventricular volumes, function and wall motion abnormalities . MoreoveThe presence of an implanted device generates image artefacts that may compromise image quality. By adapting the scan strategy, the amount of artefacts produced by the implanted pacemaker system can be kept at a minimum . VentricThe site of epicardial breakthrough on the epicardial potential map was compared to the position of the ventricular lead tip on MRI and the distance between these points was determined. The position of the RV lead tip was determined using the susceptibility artefact caused by the lead tip on the MRI images Figs.  and 3. AFor several patients, the reported distance from the lead tip to the site of earliest depolarization on the epicardial potential maps includes the distance from the lead tip in the septum to the epicardium. Septal insertion of the lead tip increases the intrinsic distance from the lead tip to the site of epicardial breakthrough. This is a limitation of the reconstruction of epicardial potentials. Therefore, the localization accuracy is probably severely underestimated in this group of patients.The anterior concentration of BSP electrodes does not allow for accurate investigation of depolarization on the posterior wall. This pilot study focussed on investigating the feasibility of performing IPM in patients with an implanted MRI-conditional pacemaker system. The current research did not describe the accuracy of localizing foci in the inferior wall of the RV or LV. Atrial stimuli were not analysed in the current study.It has been shown that prematurity of ectopic foci can affect cardiac activation patterns. This was not explored in this current study by introducing different coupled extra-stimuli during RV pacing.The accuracy of localizing epicardial breakthrough may be affected by extensive scar in patients with prior infarction or severe cardiomyopathy. For this reason and in consideration of the limited size of the study population, additional research needs to be performed to further explore the clinical benefit of IPM in combination with MRI in patients suffering from a wide range of pathologies.In this study, an IPM method using a limited number of electrodes was applied in patients with an MRI-conditional pacemaker system. For all patients, the epicardial potential distribution could be reconstructed from BSP recorded during pacing. In patients with the tip of the pacing lead close to the epicardium, a localization accuracy of 6.0 ± 1.9 mm was found. Application of this method in patients suffering from ventricular arrhythmia may enable accurate non-invasive localization of ectopic ventricular foci prior to entering the catheterization suite.Video 1This video shows a typical example of a patient with the RV lead implanted in the RVOT. First, the lead tip is identified on the MRI images. Second, the epicardial potentials map is shown. This map is reconstructed from body surface potentials recorded during ventricular pacing. The area of earliest depolarization corresponds to the region of the lead tip. Subsequently, a rapid depolarization of the right ventricular free wall is observed. (MP4 1.91 mb)Video 2This video shows a typical example of a patient with the RV lead implanted in the RV apex. After identification of the lead tip, the epicardial potentials map is shown. The area of earliest depolarization corresponds to the region of the lead tip. From this point, depolarization spreads rapidly to the basal portion of both the RV and LV. (MP4 1.42 mb)


Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction  was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine  and postconditioning pigs  versus controls (53.8 ± 4.1 %). Late MVO was significantly reduced by cyclosporine  but not postconditioning  when compared with controls (32.0 ± 16.9 %). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls  and was inversely correlated with late-MVO extent . Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine  but not postconditioning  when compared with controls (−16.4 ± 5.5 %). In the three groups, infarct size  and late MVO  were independent predictors of LVEF deterioration following ischemia/reperfusion . Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (The online version of this article (doi:10.1007/s00395-015-0475-8) contains supplementary material, which is available to authorized users. Despite complete epicardial blood flow restoration during primary coronary angioplasty in acute myocardial infarction, ischemia/reperfusion is associated with cardiomyocyte necrosis and with damage of coronary microvasculature and interstitial edema , 22, 23 The opening of mitochondrial permeability transition pore (mPTP) is considered a key event in cell death after ischemia and reperfusion , 31. MitWhether cyclosporine A or postconditioning could also have a beneficial effect on microvascular damage remains unknown. Clinical studies in this regard have limitations as the timing of CMR is not always optimal and correlation to histology is not possible. Therefore, we sought to investigate whether postconditioning or cyclosporine A infusion influence microvascular obstruction and its functional consequences in a pig model of coronary ischemia and reperfusion. If it turned out that cyclosporine A or postconditioning had a beneficial effect on microvascular obstruction, a series of additional experiments would be conducted to study their impact on myocardial edema, regional myocardial blood flow and the size of no-reflow area.All animals were treated according to National Health Guide for the Care and Use of Laboratory Animals and the study was approved by the Animal Care and Use Committee of the University of Leuven (reference number ECD P013/2009) and the Ethical Committee of the Institute of Pharmacology of the Polish Academy of Sciences (reference number 1111/2014).®100, Virbac Switzerland SA) in a dose of 8 mg/kg intramuscularly (i.m.) and Xylazine 2.5 mg/kg i.m.  before induction of anesthesia with propofol 3 mg/kg intravenously (i.v.)  and remifentanil 1 µg/kg i.v. . After intubation, anesthesia was maintained with propofol 10 mg/kg/h i.v. And remifentanil 0.3 µg/kg/min i.v. During mechanical ventilation the gas mixture, tidal volume and ventilation rate were adjusted to maintain physiologic blood gases. Clinical examination including corneal reflex and response to pain was used to monitor the adequacy of anesthesia. An 8F catheter was introduced into the carotid artery to measure blood pressure and to access coronary arteries for angiography as well as for blood sampling. Hemodynamic recordings (Millar) were done at baseline and every 30 min during ischemia and reperfusion whereas ECG was continuously monitored. Data were processed using dedicated recording and analysis software .Domestic pigs of both genders weighing 30–40 kg have been used. Pigs were pre-treated for 3 days with amiodarone (twice a day 200 mg) to reduce life-threatening arrhythmias. The day before the experiment they received 300 mg of aspirin and 300 mg of clopidogrel. Animals were pre-medicated with a combination of tiletamine and zolazepam (Zoletiln = 8), the postconditioning group (n = 9) or the cyclosporine A group (n = 8) and were subjected to 60 min of ischemia and 180 min of reperfusion  in a dose of 10 mg per kilogram body weight was administered as a peripheral i.v. injection between 15 and 10 min prior to the end of myocardial ischemia to prevent mitochondrial permeability transition pore opening during reperfusion, as previously described  were independent predictors of LVEF deterioration following ischemia/reperfusion. In total, the independent variables explained 73 % (P < 0.001) of variance associated with LVEF deterioration immediately after coronary occlusion and reperfusion, including 37 % of variance explained only by infarct size and 10 % by late MVO.Left ventricular volumes, ejection fraction, left ventricular mass, stroke volume and cardiac output at different time points are given in Table P = 0.50) and did not correlate with the size of early MVO (P = 0.22), late MVO (P = 0.27) and the no-reflow area (P = 0.12). Cyclosporine A infusion significantly improved myocardial blood flow in the late MVO territory  and in the gadolinium-hyperenhanced infarct area  as compared with control pigs. Cyclosporine A did not improve MBF in the border zone and in the remote myocardium  and lower interstitial edema  as compared with hyperenhanced area . In all pigs, microvascular obstruction area was associated with higher erythrocyte stasis (respective median (IQR) values are 2.4 (0.9–7.5) vs. 0 (0–0.05) %,  23.5–34. vs. 34.0The current study demonstrates that cyclosporine A infusion just before restoration of epicardial blood flow protects against microvascular obstruction as measured in vivo by cardiovascular magnetic resonance imaging in a pig model of ischemia and reperfusion. Despite both postconditioning and cyclosporine A infusion significantly reduced infarct size and a total time of life-threatening ventricular arrhythmia, only cyclosporine A was associated with a better preserved left ventricular function following reperfusion. Moreover, cyclosporine A infusion significantly reduced no-reflow area and improved regional myocardial blood flow in the zone of microvascular obstruction and hyperenhanced area of infarct. Finally, both infarct size and microvascular obstruction area have been shown to be independent predictors of left ventricular function deterioration after coronary occlusion and reperfusion.Postconditioning and cyclosporine A infusion are considered to have similar cardioprotective effects during I/R involving inhibition of mPTP opening and preservation of calcium retention capacity in cardiac myocytes –17. NeveATP channel activation and was mimicked by cyclosporine A [The mechanism of protection against coronary microvasculature damage associated with postconditioning or cyclosporine A and its influence on myocardial injury and left ventricular function remains poorly understood. Following I/R, microvascular perfusion defect despite patency of epicardial artery known as no-reflow phenomenon is first a consequence of extensive capillary damage with endothelial cell swelling, large membrane-bound intraluminal blebs of endothelial cells and cardiomyocyte swelling . Plugginporine A . In our Both cyclosporine A infusion and postconditioning accelerated the reduction of microvascular obstruction between 3 and 12 min after contrast injection, suggesting a faster contrast penetration due to more preserved microvascular patency and finally better reperfusion. However, the effect was more pronounced in cyclosporine A-treated pigs. The ratio of late-to-early MVO validated with the extent of no-reflow area and with the myocardial blood flow in the late-MVO territory, reflects the dynamics of contrast penetration throughout coronary microcirculation during the early phase of reperfusion. We found that the lower the ratio of late-to-early MVO the smaller the no-reflow area and the better myocardial blood flow in late-MVO territory.The cause–effect relationship between myocardial and microvascular injury is still a matter of debate. Experimental studies indicate that structural changes in the no-reflow microvasculature are preceded by and limited to the area of myocyte necrosis , 33. ThoIn the clinical settings, infarct size and microvascular obstruction are important prognostic factors for cardiovascular outcome , 53. TheOur study also allowed comparing cardiovascular magnetic resonance measurements with pathology findings. We have found that infarct size measured in vivo by gadolinium enhancement strongly correlated with triphenyltetrazolium-determined area of infarct. Recently, Robberts et al.  have shoIt was shown that postconditioning with 4 cycles of 1-min ischemia and reperfusion prior to primary coronary angioplasty in patients reduces infarct size  and atteIn conclusion, in our animal model of ischemia and reperfusion both cyclosporine A and postconditioning reduce infarct size, however, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls. Our findings indicate that only simultaneous limitation of myocardial and microvascular injury is associated with functional improvement, therefore, we suggest the use of microvascular obstruction as a surrogate endpoint in future studies in addition to infarct size.Supplementary material 1 (PDF 31 kb)Supplementary material 2 (PDF 97 kb)Below is the link to the electronic supplementary material.


Chagas disease (CD) is a frequent cause of dilated cardiomyopathy (CMP) in developing countries, leading to clinical heart failure and worse prognosis. Therefore, the development and evolution of this CMP has always been a major topic in numbers of previous studies. A comprehensive echocardiographic study of left ventricular (LV) mechanics, fully assessing myocardial contraction, has never been done before. This could help characterize and improve the understanding of the evolution of this prevalent CMP.A total of 47 chagasic and 84 control patients were included in this study and allocated in groups according to LV ejection fraction. 2D-Echocardiogram was acquired for LV mechanics analysis by speckle tracking echocardiography.Mean age of chagasic individuals was 55y and 16 (34 %) were men. Significant difference was found in global longitudinal velocity analysis, with lower values in indeterminate form. In the group with severe systolic dysfunction, a paradoxical increase in longitudinal and apical radial displacements were demonstrated. In parallel, segmental analyzes highlighted lower values of radial displacement, strain and strain rate into inferior and inferolateral walls, with increase of these values in septal and anterior walls.Chagasic CMP has a vicarious pattern of contraction in the course of its evolution, defined by reduced displacement and strain into inferior and posterior walls with paradoxical increase in septal and anterior segments. Also, lower longitudinal velocities were demonstrated in CD indeterminate form, which may indicate an incipient myocardial injury. Trypanosoma cruzi, is a serious health problem in Latin America and recently has also been emerging in non-endemic countries [Chagas disease (CD), caused by the parasite ountries . Dilatedountries . An idenountries , 4. Echoountries –8.There are few reports using other techniques besides left ventricular ejection fraction (LVEF) for chagasic patients clinical evaluation –12. MechIn this study we sought to compare the dynamics of LV contraction, through the determination of multiple echocardiographic parameters obtained by STE , segmental rotation, rotational velocity, twist/torsion) between patients with CD and control group, with and without LV systolic dysfunction.Trypanosoma cruzi and patients were enrolled into 4 groups according to LVEF: Ch1A, normal LVEF (≥55 %) and normal 12-lead electrocardiogram (ECG); Ch1B, normal LVEF (≥55 %) and ECG abnormalities suggestive of myocardial involvement by CD, such as atrioventricular block, branch or fascicular block; Ch2, mild to moderate LV dysfunction (LVEF 54–31 %); Ch3, severe LV dysfunction (LVEF ≤ 30 %). We also included control patients without CD classified into 3 groups according to LVEF . Exclusion criteria were the presence of supraventricular arrhythmias , systemic blood pressure over 180/110 mmHg, history of myocardial infarction or coronary artery disease, pacemaker, significant thyroid disease and end-stage renal failure.This is a single center prospective study. From January 2010 to August 2013, we studied 135 patients with CD and controls. CD was confirmed by at least two positive serologic tests for The institutional review board approved the study ), and all participants gave informed consent. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.Echocardiography was performed on commercially available echocardiographic platforms equipped with MS5 probe . Comprehensive 2D-Echocardiogram and Doppler evaluation was performed following the recommendations of the American Society of Echocardiography . LVEF waThe echo-STE protocol included acquisition of short axis and apical views. Parasternal short-axis views were obtained at the LV base , at LV medium portion (papillary muscles level), and at the LV apex, close to apical obliteration when there is still a clear visualization of segments. For this apical “cut”, in order to avoid quantification bias, we created another new criterion: an identification of at least a tendency to rotation of the apex. This rotation could be either in a counterclockwise direction, physiologically expected, but also in a clockwise direction, as observed in some patients with significant LV systolic dysfunction.twist = ROTapical - ROTbasal). Torsion is a normalization of LV twist to the length of LV long axis (LVtwist/LVlenth). By widely assumed convention, apical rotation had positive values and basal, negative [Left ventricular twist is the wringing motion of heart around its long axis. It is calculated as the net absolute difference between apical and basal rotations  followed transversal images. Images were acquired at a frame-rate of 40–80 fps. Three consecutive heart cycles were stored.Speckle tracking analysis was performed offline using a dedicated software . For short axis images 7–12 and for apical 3 anchor points were placed. The software automatically defined the region of interest (ROI) for the entire myocardial layer, which was divided in six color-coded segments . Careful attention was especially given to not include myocardial trabecullaes and the pericardium. Adjustments were possible. Following this step, an automatic tracking of myocardial speckles were performed and final results on the quality of this tracking were given for each color-coded segment. If there was a suboptimal tracking of one segment, adjustment was also possible. After accepting this analysis, curves were given for all variables studied and this data exported to a spreadsheet. Global values were defined as the average of segments analyzed.t test or analysis of variance (ANOVA) with post hoc Tukey HSD test. For categorical variables we used the chi-square test (χ2) or Fisher’s exact test when appropriate. To test the effect of covariates of interest, an analysis of covariance (ANCOVA) followed by Bonferroni post hoc test and multiple linear regression was performed. Analysis of interobserver and intraobserver variability were performed on six randomized patients, three with normal LVEF and three with systolic dysfunction. A value of p < 0.05 was considered statistically significant, and a confidence interval of 95 %. Statistical analysis was performed using SPSS 20.0 for Macintosh .Continuous variables are presented as mean ± standard deviation (SD) and categorical variables as numbers and proportions. Comparisons of continuous variables were performed by Student’s Among the 135 initially enrolled patients, 4 were excluded due to poor acoustic resolution (2 from CD group and 2 from control group). The final study population was composed of 131 subjects, with the following distribution: Ch1A: 8 (6 %), Ch1B: 13 (10 %), Ch2: 17 (13 %) and Ch3: 9 (7 %); C1: 58 (44 %), C2: 7 (5 %) e C3: 19 (15 %) patients. The overall feasibility for STE analysis was 97 %. Mean age of chagasic individuals was 55 years-old and 16 (34 %) were men, whereas in controls mean age was 45 years-old, 38 (45 %) men. There were few patients with hypertension (mild stage) in the chagasic groups Ch1 and Ch2. The majority of patients of the entire population was in stage I of functional symptomatic classification. Heart rate of Ch2 group was higher than its control. No other significant differences in hemodynamic parameters were observed among groups. Clinical characteristics of CD and control groups are described in Table p < 0.001, and Ch1B 3.38 ± 0.50 cm/s vs C1, p = 0.02). In order to assess a possible interaction of this find with other variables, such as hypertension and diastolic dysfunction, we performed an analysis of covariance (ANCOVA) and multiple linear regression, and no interference was found .The global values of LV mechanics analysis obtained from apical views  are described in Table p = 0.01; Table Longitudinal displacement (LD) and strain in the group with mild/moderate dysfunction were reduced. However, in the group with severe LV systolic impairment Ch3), there was a paradoxical increase of these parameters in the chagasic group . Worthy to note, we found no significant differences in basal and apical rotations, twist/torsion among groups. Data from torsional mechanics analyzes are displayed in Table The global values obtained from LV short axis  view are shown in Table p = 0.03; inf: Ch3 0.92 ± 1.72 mm vs C3 2.22 ± 1.20 mm, p = 0.03), and strain/strain rate. On the other hand, an increase of these values was demonstrated in septal and anterior wall segments . Figure Segmental analyzes were performed and two examples are shown in Tables Interobserver and intraobserver variabilities for longitudinal parameters were 6 %, and 5 %, respectively, with lower variability for longitudinal strain (3 and 4 %).For the variables obtained from short axis view, including twist and torsion, interobserver variability was 23 %. Circumferential strain rate had the lowest variability (11 %) and torsion the highest (38 %). Intraobserver variability was 19 %, with radial strain rate the lowest value (8 %) and basal rotation the highest (32 %).This is the first study to fully assess myocardial contraction mechanics in CD throughout its evolution. Although there are a large number of studies using general echocardiography in CD, a recent search using major scientific databases disclosed only two studies that used this relative novel echocardiographic tool (STE) and were similar to ours, conducted by García-Álvarez et al.  and BarbGroups in our study were relatively homogeneous, with a few differences in demographics, clinical and echocardiographic parameters. To note, our patients with CD and normal systolic function (Ch1A and Ch1B) were older than our control healthy volunteers (C1), with a higher frequency of hypertension and use of inhibitor of angiotensin converting enzyme. Hypertension, when present in this study was in a mild stage. It is noteworthy that we observed no significant difference on the blood pressure at inclusion examination.Chagasic patients in the chronic indeterminate form (Ch1A group) had lower longitudinal velocities with statistically significant difference compared to its control group (C1), even after statistical adjusts for hypertension and diastolic dysfunction. This is a very interesting finding and may indicate an incipient myocardial involvement by CD.A comprehensive and detailed analysis of LV mechanics aimed in our study made it possible to describe the pattern of myocardial contraction in CD. This was evident in the group with severe LV systolic impairment. Segments classically affected by CD, as in inferior and lateral walls, had lower values of radial displacement and deformation (strain/SR). A predilection of CD to affect inferior and inferolateral walls was also demonstrated by Barbosa et al. in their study STE in asymptomatic patients with CD with normal LV systolic function . This auPhysiopathogenesis of CD is still not fully understood. Evidences point that a predominant affection of inferior, lateral and apical left ventricular segments may reside on the fact that there is a significant microcirculatory disarrangement on peripheral vascular beds throughout chagasic CMP evolution. In these “watershed zones” located in these myocardial segments, there would be focal ischemia, perpetuating a chronic inflammation, leading to fibrosis , 27. Clap = 0.04). All these findings were not confirmed in our study. Noteworthy is the low values of twist found by this author, mainly due to lower apical rotation  [García-Álvarez et al. described lower values of radial strain in the middle segment of inferior wall and found differences in LV twist in CD indeterminate form compared to its control group  . Compari, +7.6°) –34.Small number of patients with CD allocated to each subgroup was a limitation of our study. However, it is noteworthy that we performed a segment-to-segment analysis which involved a large number of myocardial segments in each subgroup and this enabled our study to disclose the significant difference among variables.The subjectivity of echocardiography can bring biases of quantification. This is exemplified when referring to the “cutting” level of the LV in its apical short axis, which has no anatomical landmark. So, small variations in the level of image acquisition can lead to distorted values. Our new criterion created for this study – an identification of at least a tendency to rotation of the apex – tried to preclude this issue.Despite STE method is validated in the literature, it is still an evolving technique, and improvements, such as the accuracy of the tracking, are still needed.Left ventricular systolic mechanics analysis disclosed a vicarious pattern of contraction in the course of chagasic CMP evolution. CD with LV mild/moderate systolic impairment had a global reduction in all systolic parameters. However, a major reduction of displacement and strain into inferior and posterior walls had an opposite paradoxical increase of these parameters into septal and anterior segments. This may help defining a non-ischemicMP etiology, providing robust elements to point to a chagasic cause where this disease is prevalent. Additionally, patients in the indeterminate form of CD presented with lower longitudinal velocities, which may indicate an incipient myocardial injury.CD, Chagas disease; CMP, cardiomyopathy; LVEF, left ventricular ejection fraction; STE, speckle tracking echocardiography; A4C, apical four chambers; A2C, apical two chambers; A3C; apical theee chambers or long-axis; LD, longitudinal displacement; LS, longitudinal strain; LSR, longitudional strain rate; RD, radial displacement; RS; radial strain; RSR, radial strain rate; CS, circumferential strain; CSR, circumferential strain rate


Cardiogenic shock which corresponds to an acute state of circulatory failure due to impairment of myocardial contractility is a very rare disease in children, even more than in adults. To date, no international recommendations regarding its management in critically ill children are available. An experts’ recommendations in adult population have recently been made :52, The online version of this article (doi:10.1186/s13613-016-0111-2) contains supplementary material, which is available to authorized users. Cardiogenic shock is an acute state of circulatory failure due to impairment of myocardial contractility. In children, the clinical signs of cardiac failure are tachycardia, dyspnea, and hepatomegaly, together with global signs related to a decrease of cardiac output. Cardiogenic shock represents 5–13 % of diagnosed cases of shock in pediatric emergencies . It is tManagement and monitoring of cardiogenic shock in childhood differ between anatomically normal heart and congenital heart disease. Recommendations made in this document are addressed to children without congenital heart disease; it is important in the case of children with heart disease who decompensates to be in contact with pediatric cardiologists to optimize management. Cardiogenic shock occurs when heart and circulation are no longer able to adapt to the situation and is characterized by severely impaired myocardial contractility, increased preload, severely impaired myocardial compliance, increased afterload, and an abnormally and persistently high heart rate. Decompensation may occur and manifests as a drop in blood pressure and/or cardiac output with inadequate tissue perfusion, as this is the final goal of cardiovascular performance, and the onset of anaerobic metabolism with the production of lactic acid. Unless treated, cardiogenic shock leads to multiple organ failure then progresses rapidly to death.Even if the literature is poor regarding strong evidences in management of cardiogenic shock, we report, in this article, recommendations built by pediatricians and anesthesiologists, experts in the topic of cardiogenic shock. Process of recommendations’ elaboration permitted us to avoid making the recommendations only based on own experience. The recommendations cover four major fields of application such as: recognition of the early signs of shock and the patient pathway, management principles and therapeutic goals, monitoring hemodynamic and biological variables, and circulatory support .Three pathophysiological states have been described for cardiogenic shock Fig. :Fig. 1CaCold and wet: reduced myocardial contractility and increased left ventricular filling pressure (systolic and diastolic dysfunction).Cold and dry: reduced myocardial contractility and low left ventricular filling pressure (systolic dysfunction).Warm and wet: normal myocardial contractility and high left ventricular filling pressure (diastolic dysfunction).Impaired consciousness, arterial hypotension, and respiratory distress with a fall in oxygen saturation are the early signs of decompensated heart failure and cardiogenic shock –14.TableSuch signs are based on the patient’s medical/surgical history , but also on blood pressure measurements in all limbs, as well as the presence of heart murmur, arrhythmia, or sepsis.Chest X-rays , ECGs , and transthoracic echocardiograms are useful for diagnostic, etiological, therapeutic, and prognostic purposes.In addition to the risk of multiple organ failure and death, cardiogenic shock is sometimes associated with cardiorenal syndrome , which leads to longer hospital stays, the need for circulatory support, and an increased death rate .The aim of initial patient management is to restore adequate oxygen delivery to peripheral tissues. This relies on emergency support , optimizing ventilation/gas exchange (oxygen therapy ± noninvasive or invasive ventilation with a saturation objective of >95 % except in cyanotic heart disease patients), optimizing the preload and afterload , and treating curable causes .strong agreement).All patients with cardiogenic shock should be transferred to PICU (strong agreement).Children with cardiogenic shock should be managed by a chain of specialized medical teams which adapt their care to the real or potential gravity of the patient throughout his/her stay in care. This medical chain should be clearly identified by all healthcare actors  (strong agreement).A telephone hotline to an “expert center” providing specialized responses should be available 24/24 (strong agreement).It is strongly advised that regional health agencies officially designate “expert centers” (strong agreement).The following multidisciplinary expertise should be available in such expert centers: pediatric medical and interventional cardiology, pediatric anesthesia, pediatric thoracic, vascular and cardiac surgery, pediatric intensive care, radiology , mobile circulatory support unit (strong agreement).Basic or advanced European pediatric life support resuscitation, either prior to arrival or at the hospital should be used to reduce morbidity and mortality of cardiogenic shock (strong agreement).It is probably not advisable to use high doses of adrenaline (≥30 µg/kg) during resuscitation compared with usual doses (strong agreement).Early goal-directed therapy should be based on clinical  and laboratory  variables as well as echocardiogram (strong agreement).Once the acute phase of cardiogenic shock has been relieved, the patient should be prescribed appropriate oral therapy to treat cardiac insufficiency and should be closely monitored ] and functional morbidity [OR 0.13 (0.04–0.41)] . No benestrong agreement).Fluid resuscitation should only be indicated in patients with cardiogenic shock after clinical assessment (preload insufficiency); it is advised that echocardiographic evaluation be used during such assessment (strong agreement).Fluid resuscitation with colloids and/or crystalloids should not be used in patients with cardiogenic shock  related to fluid overload .strong agreement).In children with fluid overload and ventricular dysfunction, diuretics (such as furosemide) should be used to return to euvolemic state while monitoring clinical criteria and measuring the cardiac output .It is probably not advisable to use venous perfusions of nesiritide (recombinant BNP) in children with cardiogenic shock (strong agreement).It is probably not advisable to use tolvaptan, a selective antagonist of the arginine vasopressin receptors (V2) that is given orally in children with cardiogenic shock .Dobutamine should be used at a dose of 5–20 µg/kg/min in cases of cardiogenic shock with maintained blood pressure so as to restore cardiac output (strong agreement).It is probably advisable to use milrinone (continuous perfusion of 0.5–0.75 µg/kg/min) as an alternative to dobutamine in children with cardiogenic shock, especially in post-cardiac surgery patients and in cases with impaired right ventricle function and/or associated pulmonary arterial hypertension (strong agreement).Levosimendan (continuous perfusion of 0.1–0.2 µg/kg/min) may be used as second-line treatment in patients with cardiogenic shock who do not respond to the usual therapy (dobutamine or milrinone with or without diuretics), especially for postoperative management after cardiac surgery (Dobutamine is still the gold standard inotrope for the dynamic assessment of the cardiovascular system and is used as the reference inotrope in comparative studies . After c2) and reduces systemic and pulmonary vascular resistance and the mean pulmonary arterial pressure 30 min, 1 h, and 2 h after a loading dose of 50 µg/kg . In 218 post-cardiac surgery pediatric patients, Trittenwein et al. [cvO2 <60 %, or if arterial lactate levels >18 mmol/L and ScvO2 >60 % on admission to intensive care (p < 0.05). The authors suggest that these levels be used as postoperative criteria for ECMO implementation.No prospective randomized studies have been performed to define specific criteria for ECMO implementation in children with cardiogenic shock. Based on data from the ELSO registry in 2005, Thiagarajan et al.  reportedt et al.  demonstrt et al. , 131, whn et al.  reportedstrong agreement).ECMO should be implemented by a team of trained healthcare professionals (strong agreement).Patients treated with ECMO should be transferred to an expert center , on-site therapeutic means and hemodynamic assessment measures, and the response time of the mobile circulatory support unit should be taken into account.strong agreement).Candidate pediatric ECMO reference centers should perform at least 15–20 ECMOs on pediatric patients per year (No randomized studies have been performed on expert pediatric ECMO centers.p = 0.01), whereas low ECMO activity (<15/year) was a risk factor for in-hospital mortality .An expert center must have a multidisciplinary technical platform that can ensure complete care of pediatric patients treated with ECMO for both medical and surgical indications. In a study based on 3867 pediatric congenital cardiopathy patients treated with ECMO, Karamlou et al.  showed tWe report here experts’ recommendations regarding management of children with cardiogenic shock. We hope this work will help healthcare professionals in their daily practice. We propose in conclusion a decision tree Fig.  for the


ANKRD1, ANKRD2, TRIM63, TRIM55, NBR1, MLP, FHL2, and TCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevated ANKRD1 expression levels marked transition from NYHA < IV to NYHA IV. ANKRD1 expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardial ANKRD1 and serum adiponectin correlated with low BAX/BCL-2 ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM. ANKRD1 expression correlated with reduced cardiac contractility and compliance. The association of ANKRD1 with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands ( Despite intensive search for therapeutic interventions, idiopathic dilated cardiomyopathy (IDCM) remains the major cause of heart failure eventually leading to heart transplantation. Limited availability of donor hearts results in long waiting times before transplantation can be performed. Many patients with end-stage heart failure perish before a donor heart becomes available. Management of patients awaiting transplantation is demanding, because some of them remain stable while others deteriorate quickly . However ANKRD1 expression pattern were found to be most informative: ANKRD1 levels were associated with decreased cardiac contractility and compliance. ANKRD1 gene encodes an ankyrin repeat-domain containing protein 1 . Ankrd1 belongs to a family muscle ankyrin repeat proteins, interacting with titin in a stretch-dependent manner: upon mechanical stretch it translocates to the nucleus, where it acts as transcription cofactor [ ANKRD1 upregulation was observed in increased stretch states such as experimental pressure overload [ ANKRD1 were found to be associated with dilated [Myocyte apoptosis was shown to be a contributor to the development of heart failure (HF) , whereascofactor . Ventricoverload  or clinioverload  and arrhoverload . Moreove dilated  and hype dilated . Functio dilated  and hypo dilated  and is d dilated , 13 anth dilated . In thisβ-blockers, mineralocorticoid receptors blockers, digitalis , diuretics, anticoagulant , and antiarrhythmics (class III: amiodarone) . Clinical decision about possible treatment with cardiac resynchronization therapy, radiofrequency ablation, or implantation of a left ventricular assist device or implantable cardioverter-defibrillator was made after coronary angiography and EMB. All patients gave written informed consent to this study, including cardiac catheterisation and EMB. The study was approved by Lithuanian Bioethics Committee (Protocol number 158200-2011/09) and conducted in compliance with the Declaration of Helsinki.Our study cohort was composed of patients admitted to the Vilnius University Hospital during 2011–2013 with suspected diagnosis of IDCM. All patients underwent a careful history and physical examination, as well as routine laboratory studies, including B-type natriuretic peptide (BNP), adiponectin, and cardiac troponin T (hsTnT). 23 patients were selected because of a reduced left ventricular ejection fraction (LVEF < 45%) in the absence of significant coronary artery disease (stenosis of coronary arteries of less than 50%), a history of myocardial infarction, and other specific heart muscle diseases , all consistent with primary IDCM. IDCM diagnosis was confirmed by histological analysis of endomyocardial biopsies (EMB). Patients who were diagnosed as having acute myocarditis according to histological evidence were excluded from the present study. NYHA class was assigned by a clinician unaware of patient echocardiographic investigation. All patients received maximal pharmacological heart failure therapy according to European Society of Cardiology guidelines: ACE inhibitors or angiotensin receptors blockers, Echocardiographic evaluation was performed 1 day before cardiac catheterisation by GE Vivid 7 and 9 ultrasound system by an investigator blinded for the study objectives. The standard LV apical  views and parasternal short axis views at mid-papillary level were acquired at 70–90 frames/s. Conventional echocardiographic parameters such as left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), velocities of E and A waves (E and A) and their ratio (E/A), and E deceleration time (DcT) were obtained. All images were stored digitally for subsequent offline analysis. Quantification of myocardial deformation values was performed by 2D speckle tracking using Echopac PCBT08  software. After the manual selection, speckles were assumed automatically and then confirmed by the investigator. By the semiautomatic postprocessing longitudinal , circumferential, and radial strain (RS) and strain rate parameters were extracted. Mean pulmonary artery (PA) pressure, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR) were measured and EMB was taken during right heart catheterization. Biopsy specimens were immediately placed to −70°C until further processing.Ct method could not be used for quantification of transcript levels. Therefore relative transcript abundances were quantified using Ct method (Ct  gene  of  interest − Ct  S18  rRNA). Transcript levels in this work are expressed as negative Ct values; thus higher −Ct values denote higher mRNA levels whereas negative Ct values represent genes that are less abundant compared with the reference gene. Bax/Bcl-2 ratios were calculated as Ct((Ct  Bax − Ct  S18  rRNA)−(Ct  Bcl-2 − Ct  S18  rRNA)) corresponding to relative expression ratio [RNA from EMB samples was extracted using RNeasy fibrous tissue minikit according to provided protocol (Qiagen). Tissue was directly homogenized in lysis buffer using Ultra-Turrax device. RNA was reverse transcribed using High Capacity RNA-to-cDNA Kit primed with mixture of random and poly-dT primers (Invitrogen). Transcripts were quantified using TaqMan Gene Expression assay on Real-Time Stratagene MX 3005P machine following manufacturer recommendations. Amplification efficiency validated TaqMan probes (Supplementary Table  2) used in this work are presented in on ratio .Levels of activated caspase-3 in EMB samples were determined using ELISA, specific for the activated protein form . Tissue samples were lysed by sonification in RIPA lysis buffer  supplemented with phosphatase and protease inhibitors according to manufacturer's recommendations . Protein content in clarified lysates was measured using modified Lowry protein assay using bovine serum albumin as standard according to the provided protocol . Analyte concentration was expressed as ng/mg of total protein.U test was used to assess differences between two independent groups. Pearson product-moment correlation coefficient was used to evaluate linear dependence between values. If otherwise not indicated, a value of P < 0.05 was taken as significant (two-tailed).Statistical analysis was performed using SPSS 17 software. Nonparametric Mann-Whitney  ANKRD1, ANKRD2, TRIM63, TRIM55, NBR1, MLP, FHL2, and TCAP in EMB biopsies from end-stage IDCM patient cohort to test their potential roles in titin-based cellular stress transmission. Clinically, we surveyed patients with significantly reduced LVEF, elevated BNP and TnT values, elevated intracardiac pressures, and impaired relaxation . ANKRD1 had the highest expression levels compared to other titin ligands and the most profound 6-fold induction  in NYHA IV patients as compared to NYHA <IV patients. Therefore, ANKRD1 expression pattern was the most sensitive to the disease progression and was chosen for the further analysis.Here, we determined the transcript levels oflaxation . Patientlaxation . Out of  ANKRD1 expression we looked for further clinical parameters different between NYHA class >IV and <IV. Statistically significant differences between NYHA <IV and NYHA IV groups were only detected for parameters of systolic strain  compared to moderate HF (NYHA < IV) patients. Clinically, severe HF patients had notably poorer systolic strain rates indicating reduced cardiac contractility. Our data indicate that myocardial strain parameters are superior to LV ejection fraction and chamber diameter, intracardiac pressure, and relaxation measures in detecting the severity of heart failure as estimated by NYHA functional class. Our findings are in line with previous studies where myocardial strain predicted rapid HF progression in end-stage IDCM patients [ ANKRD1 expression correlated not only with reduced LV contractility, but also with increased cardiac stiffness; ANKRD1 expression positively correlated with shortening of E wave deceleration time, marking restrictive filling pattern—the most powerful independent prognostic indicator of poor outcome or transplantation in DCM patients [ ANKRD1 levels in IDCM patients are associated with progression of LV remodeling, resulting in reduced cardiac contractility and compliance. In DCM, myocyte apoptosis is related to LV dysfunction [ ANKRD1 expression and apoptotic status in the myocardium. We found that tissue samples more susceptible to apoptosis (high BAX/BCL-2 ratio) had lower ANKRD1 levels than apoptosis-resistant samples (low BAX/BCL-2 ratio) implying that ANKRD1 could act as myocyte survival factor. However, counterintuitively the group with less impaired cardiac contractility (above median RS) was more prone to apoptosis than low RS group. In addition, impaired contractility was associated with higher BAX/BCL-2 ratios and elevated levels of key apoptosis-executing enzyme [ BAX/BCL-2 ratio in hearts with severely impaired contractility was mainly due to increased levels of the survival factor Bcl-2. Moreover, insensitivity to apoptosis was associated with increased serum adiponectin levels, a predictor for mortality in patients with chronic HF [ BAX/BCL-2 ratio in end-stage IDCM patients, as it has antiapoptotic effects in myocardium [Genes coding for titin binding proteins has been suggested to act as members of a titin filament based stress sensing mechanoptotic machinery in previous mouse work . Here, wpatients . Moreovepatients . Taken tfunction  and appefunction , 19. Finfunction  and hypofunction . Therefog enzyme  and actig enzyme . In agreg enzyme , we founronic HF . Possiblocardium . ANKRD1 transcript and launch Ankrd1-mediated survival cascades. Hypothetically, ANKRD1 and adiponectin or their agonists could be used as heart-specific antiapoptotic agents in treatment of IDCM.Speculatively, stretch-sensing and prosurvival properties of Ankrd1 could be responsible for the observed antiapoptotic response in terminal IDCM stages . LV remo ANKRD1 [ ANKRD1 is very likely to be universal pathophysiological as it was described in controlled increased stretch states such as experimental pressure overload [This study has some limitations which have to be pointed out. The study cohort consisted of patients with advanced HF (NYHA classes III-IV); thus future research would be needed to confirm the validity of observed clinical correlations in patients with mild HF (NYHA I-II). Recent studies have demonstrated that genetic alterations of titin  and ANKR ANKRD1 , 34 are  ANKRD1 . Thus, ioverload  and not  ANKRD1 transcript quantification is sensitive test for monitoring progression of advanced IDCM stages. Moreover, quantitative RT-PCR might be method of choice to quantify ANKRD1 levels, when using minute EMB samples.Although transcript levels do not always represent changes in protein concentration, our data suggest that ANKRD1 expression and deterioration of cardiac contractility and compliance in IDCM patients. Therefore, elevated ANKRD1 expression could serve as potential clinical marker to uncover a coming need to plan heart transplantation in end-stage HF patients. Further research is warranted on the functional roles of ANKRD1 induction in IDCM associated apoptosis.In conclusion, expression profiling of selected mechanoptotic machinery members revealed association between increasedSupplementary Table 1 Pharmacological heart failure therpay of studied cohort. Supplementary Table 2 List of Taqman probes used in this study.


Atrial fibrillation (AF) is common in patients with heart failure (HF) and worsens their prognosis. Vulnerability to changes in loading is an important factor in the development of AF and is strongly influenced by ventricular stiffness and ventriculo-arterial interaction. The aim of this study was to investigate predictors of AF development in patients with HF.We studied 349 patients with stable HF. The following parameters of ventricular stiffness and ventriculo-arterial interaction were derived from echo-Doppler measurements: left ventricular (LV) diastolic elastance (Ed), effective arterial elastance (Ea), LV end-systolic elastance (Ees) and ventricular–vascular coupling index (VVI).p = 0.018). Ea and VVI were also associated with new-onset AF .AF occurred in 57 (16.3 %) patients over a median follow up of 30.3 months. Echo-Doppler–derived parameters of ventricular stiffness and ventriculo-arterial interaction were closely associated with HF severity. Ed was independently associated with AF after adjustment for age, hypertension, diabetes mellitus, and left atrial volume index  is the strongest predictor of new-onset AF in HF patients.The online version of this article (doi:10.1186/s12947-016-0050-y) contains supplementary material, which is available to authorized users. Heart failure (HF) and atrial fibrillation (AF) each affect 1–2 % of the general population and the prevalence of both increases with age , 4. SincWe retrospectively investigated 349 consecutive patients  with stable HF with normal sinus rhythm who had undergone echocardiography between January 2007 and December 2008 in our institution. Reduced left ventricular (LV) contractility was defined as either a reduced ejection fraction (EF) (EF < 40 %) or a borderline EF (40 % ≤ EF < 50 %), based on two-dimensional echocardiography . ExclusiWe reviewed medical history, physical examinations, laboratory tests, medication records, chest radiographs, 12-lead ECG, and echocardiography findings in all patients. We followed the study population for the development of AF via a review of their medical records. New-onset AF was defined as the first episode of paroxysmal or persistent AF, as documented by resting ECG or 24-h Holter monitoring, during the follow-up period. When the patient presented symptoms such as palpitations or dizziness, 24-h Holter monitoring was performed. Paroxysmal AF was defined as AF that terminated spontaneously within seven days, and persistent AF as continuous AF that was sustained beyond seven days . Study pTwo-dimensional, pulsed-Doppler, and tissue-Doppler echocardiographic examinations were performed using an appropriate ultrasound device . Standard 2-dimensional measurements—LV diastolic and systolic dimension, ventricular septum and posterior wall thicknesses, left atrial (LA) volume, and LV outflow tract diameter—were obtained, based on the recommendations of the American Society of Echocardiography . LVEF waFor the evaluation of the vulnerability of the LV, we measured ventricular stiffness and end-systolic ventriculo-arterial interaction using echo-Doppler , 9. VentU test were used for their comparisons.Baseline characteristics were summarized for all participants using standard descriptive statistics. Continuous variables are presented as mean ± standard deviation and categorical variables as number and percentage. Baseline characteristics of groups were compared using independent t-tests for continuous variables and chi-square tests for categorical variables. Variables without normal distribution were presented as median (inter-quartile range) and Mann-Whitney p-value was <0.05 when using two-sided tests. All statistical analyses were performed using SPSS 18.0 .Linear regression analyses were performed to determine the association between echo-derived parameters and the HF severity, estimated by EF and levels of log-transformed brain natriuretic peptide (BNP). To achieve a constant variance, BNP values were transformed logarithmically. Cox proportional hazard models were used to determine the association between Ed, Ees, Ea, and VVI, and the development of new-onset AF. Adjustment variables were selected based on the differences between two groups (AF vs. sinus rhythm) and clinical rationale; they included age, LA volume index(LAVI), and underlying disease. We also used receiver operating characteristic curves to derive cutoff values for predictors. Time-to-event data are reported and displayed using the Gehan’s generalized Wilcoxon method, with comparisons between groups performed using the log-rank testDifferences were considered statistically significant if the Patient characteristics and echocardiographic parameters are presented in Table p = 0.003) and had a higher prevalence of hypertension  and diabetes . The rate of ischemic cardiomyopathy did not differ between the two groups. The new-onset AF group used more diuretics  than the sinus rhythm group (Table p = 0.011) in patients with AF.The new-onset AF group was older , LV systolic function , LV mass index , A , or e’ . However, the new-onset AF group had a larger LA volume index , a higher E , and a higher E/e’ ratio . A’ was significantly lower in the new-onset AF group  (Table p = 0.009) in the new-onset AF group. Ees, Ea, and VVI did not differ significantly between the two groups.There was no difference in LV end-diastolic diameter  and Ea . In addition, BNP level was significantly correlated with Ed , Ees  and Ea  . After adjustment for age, hypertension, diabetes mellitus, use of diuretics and LAVI, EF was not correlated with AF . Ed was also significantly associated with new-onset AF, with a greater than 10-fold risk in an unadjusted model . This association remained significant after adjustment for age, hypertension, diabetes mellitus, use of diuretics and LAVI, . Ea and VVI were associated with new-onset AF after adjustment for age, hypertension, diabetes mellitus, use of diuretics and LAVI   . Lower EF was significantly associated with new-onset AF  .Further evaluation was performed to determine the power of Ed in predicting AF occurrence. The optimal cutoff value to predict AF was an Ed value of 0.33, with corresponding sensitivity and specificity values of 71 and 58 %, respectively  Ventricular stiffness and ventriculo-arterial interaction could be measured by echo Doppler, and (2) Ed, Ea and VVI were closely correlated with new-onset AF in patients with HF.AF is the most common arrhythmia , 9 and fp < 0.001). This finding suggests that these patients were clinically identified as having volume overload or elevated LV filling pressure and were being treated as such. Recently, Cambell et al. showed that renal impairment was strong predictor of AF in patients with HF and should be regularly screened. In our study, prevalence of chronic kidney disease was not different between AF group and sinus rhythm group.The new-onset AF group was receiving diuretics at a statistically significantly higher rate  correlates well with LV filling pressure in heart failure; however, myocardial relaxation and filling pressure could affect the mitral E velocity. The mitral e’ velocity reflects relaxation of the myocardium and the E/e’ ratio correlates well with LV filling pressure or pulmonary capillary wedge pressure –23. In tIn HF patients, increased ventricular stiffness induces diastolic dysfunction, thereby causing an elevation of LV filling pressure and increasing vulnerability to an acute loading change . E/e’ isIncreased afterload is also important in the pathophysiology of HF . The Ea The present study had some limitations. First, since it was a single-center study with a retrospective design, only limited data analysis was possible and follow-up durations were arbitrary. Second, the occurrence of new-onset AF might have been underestimated. Capturing AF is notoriously difficult, unless careful transtelephonic monitoring or regular Holter recordings can be performed. We know that relying on symptomatic presentation will underestimate the occurrence of AF, given that much of AF is asymptomatic. There is no way of knowing whether patients in the “sinus rhythm” group actually had paroxysmal AF or not. Finally, the male predominance in the study patients was a potential limitation, in that it did not reflect the general clinical HF population; however, this is a common failing shared with many other contemporary HF studies.Echo-Doppler–derived indexes of ventricular stiffness and ventriculo-arterial coupling are associated with HF severity and are important predictors of new-onset AF in patients with HF. Therefore, HF patients with increased ventricular stiffness may need close observation for the development of AF, using techniques such as frequent Holter monitoring.