Mitral valve regurgitation in dogs is a common cardiac disease. The standard treatment for this disease is medical therapy, but as the condition progresses, it leads to congestive heart failure. In recent years, surgical treatment of mitral valve regurgitation in dogs has emerged, but the recommended procedure is invasive and time-consuming. Therefore, a less invasive and time-consuming surgical procedure is necessary for future utilization in the treatment of mitral valve regurgitation. Recently, a novel transcatheter edge-to-edge mitral valve repair device became available and is anticipated to be a minimally invasive and less time-consuming device, but there are no data available on the hemodynamic changes after its cardiac implantation.Mitral valve regurgitation is a common canine heart disease. Transcatheter Edge-to-Edge Repair (TEER) is a transcatheter, edge-to-edge mitral repair device that uses a hybrid approach. No detailed information has been published on the hemodynamic effect of TEER on cardiac function. The aim of this report is to provide a longitudinal observation of the cardiac functional changes observed after TEER implantation in normal dogs using traditional, two-dimensional speckle tracking, and color M-mode echocardiographic methods. In the current report, TEER was implanted into two healthy dogs under general anesthesia. An echocardiographic examination was performed at baseline and weekly postoperative follow-ups were conducted until the fourth week. Successful TEER implantation was achieved with a short operation time (98 and 63 min) in the two dogs. Functional mitral valve regurgitation, elevated E/e’ ratio, elevated radial strain, and stable intraventricular pressure gradients (IVPG) were observed after the operation in the dogs. Mild non progressive mitral valve stenosis was observed in both dogs. TEER is a minimally invasive method for mitral valve surgery that necessitates more clinical trials. With longitudinal observation of heart function using novel approaches, better outcomes will be expected. Mitral valve disease (MVD) is the most common cardiac disease in dogs, especially in small breeds. Up to 75% of dogs with clinical signs of congestive heart failure (CHF) suffer from mitral valve regurgitation (MR) which is caused by the myxomatous degeneration of the valve leaflets and chordae tendineae . The recThe surgical procedures to manage this condition in humans require cardiopulmonary bypass and have a high risk of complications. In human medicine, percutaneous MV repair using the MitraClip® system  was established in 2008 and has been demonstrated to be safe, ameliorates clinical symptoms and reduces the durations of hospitalization and mortality by addressing severe MV functional defects in high-risk surgical patients suffering from CHF . UnfortuTranscatheter Edge-to-Edge Repair (TEER) is an easy-to-operate, transcatheter MV repair system for use in humans and dogs using a hybrid approach . This deRecent echocardiographic approaches such as two-dimensional speckle tracking echocardiography (2D-STE) and intraventricular pressure gradients (IVPG) calculated from color M-mode echocardiography create a breakthrough in cardiology research for the early diagnosis of cardiac dysfunctions, as compared with other traditional methods ,17,18. IImplantation of the TEER was performed in two female beagles, aged 2 and 2.5 years and weighing 8.6 and 10.3 kg, respectively. These two dogs were healthy, based on physical examinations, hematobiochemical profile, conventional echocardiography, and urinalysis. The detailed procedure of the surgical approach has been previously described . BrieflyEchocardiographic examination was performed using a Hitachi ProSound Premier 75CV  or Hitachi LISENDO 880  ultrasound system equipped with a 1–15 MHz TEE probe. Standard conventional echocardiography from both right and left sides including the ordinary long axis and short-axis views was performed for each dog at the baseline (preoperative) and 3 times postoperative  according to De Madron et al. . EchocarThe 2D-STE was performed from the right parasternal short-axis view at the papillary muscle level and left parasternal apical four-chamber view. Digital cine-loops of three consecutive heart cycles with the frame rate set at 70–110 frames/s were captured from all dogs and saved as DICOM files for further processing using in-house code software . By using DAS-RS1, the short axis analysis and free use methods of video processing were used for short axis and long axis 2DSTE evaluation, respectively. The endocardium and the epicardium were outlined automatically at end-systole and end-diastole. The tracing borders were manually edited to ensure that the visualized real wall motion and the whole wall thickness were incorporated into the region of interest used in the frame-by-frame basis analysis. From the short-axis view, segmentation with an angular interval of 60° divided the LV into the following 6 segments; anterior, anterior septal, anterior lateral, inferior, inferior septal, inferior lateral. Based on tracing of these 6 segments, we reported the left ventricular global circumferential strain (GCS), global circumferential strain rate (GCSR) and global radial strain (GRS). From the left apical four-chamber view, longitudinal strain (LS) and longitudinal strain rate (LSR) were assessed .Intraventricular pressure gradient (IVPG) was obtained from the apical four-chamber view through CMME and analyzed with homemade software in MATLAB . DetailsThe operation times for each operation were 98 and 63 min. The dogs recovered from the general anesthesia uneventfully, and no adverse cardiac symptoms from the operation were observed. Three weeks after TEER implantation, dog 1 was diagnosed with mild pulmonary edema by chest X-ray, however, because no related symptoms were observed, medication was not prescribed. No arrhythmia was observed during the operation. There was a single ventricular premature complex (VPC) after surgery in both cases; however, no treatment was required because the related symptoms were not observed and there were no cardiac disturbances observed after VPC.The detailed echocardiographic parameters are listed in MVD is the most common cardiac disease in dogs. The current approach for the surgical treatment of MVD is valvuloplasty under extracorporeal circulation conditions, which is greatly invasive and time-consuming ,10. InstIn the current report, the TEER, an example of a minimally invasive device, was successfully implanted in two healthy dogs. The operation time was approximately one hour to one and a half hours, which is much shorter than the time required for valvuloplasty under extracorporeal circulation conditions ,23,24. AThe use of TEE is necessary to guide device implantation. In this report, device implantation was performed using three-dimensional (3D) TEE in one case and with 2D TEE in the other case. The use of 3D TEE is advantageous for the detection of the position of the device in the heart; however, 2D TEE can also be used, although changing the view is necessary for successful implantation. Taking into consideration that 3D TEE is expensive, the use of 2D TEE is more realistic and it is more likely to be adopted by more facilities.Similarly to the MitraClip, the TEER clamps the anterior and posterior mitral leaflets to reduce the regurgitation . The claE- and A-waves have been reported to serve as indicators of increased left ventricle filling pressures and diastolic dysfunction, respectively . The preThe E/e’ ratio has been reported to correlate with the pulmonary capillary wedge pressure when the mitral inflow passes through the MV . With thIn the two dogs, we observed an increase in FS% and radial strain. FS is widely used to evaluate the systolic function in dogs. However, FS does not accurately detect it because it only observes myocardial contraction in a radial direction at a pair of specific myocardial segments, whereas in fact, myocardial shortening occurs in different directions . In addiThe correlation between E/e’ and the pulmonary capillary wedge pressure can be challenging in patients with altered MV geometry. IVPG is the force that suctions the blood from the left atrium into the left ventricle during early diastole. The basal part of IVPG has been shown to correlate with left atrium pressure, and mid-to-apical IVPG has been correlated with myocardium movement . In dog The current report has some limitations. This report only includes two healthy dogs. The occurrence of clinical abnormalities, including mitral stenosis, is expected because the orifice was normal before surgery. In addition, this approach might be helpful in mitral valve disease, which is associated with the large MV orifice observed in MMVD. Currently, surgical correction is the only option for fixing the enlarged MV orifice in clinic. TEER provided us with a fixing tool that is easy to manipulate. The previous study proved the efficiency of the device in the case of MMVD . HoweverTEER provides a minimally invasive method for mitral valve repair that warrants further clinical trials in dogs with mitral valve disease to suppress volume overload. The narrowing of the mitral valve, caused by TEER, might be beneficial to MMVD patients. Basal IVPG appears to be a potential index for evaluating postoperative congestion.


Cardiac structure contouring is a time consuming and tedious manual activity used for radiotherapeutic dose toxicity planning. We developed an automatic cardiac structure segmentation pipeline for use in low-dose non-contrast planning CT based on deep learning algorithms for small datasets. Fifty CT scans were retrospectively selected and the whole heart, ventricles and atria were contoured. A two stage deep learning pipeline was trained on 41 non contrast planning CTs, tuned with 3 CT scans and validated on 6 CT scans. In the first stage, An InceptionResNetV2 network was used to identify the slices that contained cardiac structures. The second stage consisted of three deep learning models trained on the images containing cardiac structures to segment the structures. The three deep learning models predicted the segmentations/contours on axial, coronal and sagittal images and are combined to create the final prediction. The final accuracy of the pipeline was quantified on 6 volumes by calculating the Dice similarity coefficient (DC), 95% Hausdorff distance (95% HD) and volume ratios between predicted and ground truth volumes. Median DC and 95% HD of 0.96, 0.88, 0.92, 0.80 and 0.82, and 1.86, 2.98, 2.02, 6.16 and 6.46 were achieved for the whole heart, right and left ventricle, and right and left atria respectively. The median differences in volume were -4, -1, + 5, -16 and -20% for the whole heart, right and left ventricle, and right and left atria respectively. The automatic contouring pipeline achieves good results for whole heart and ventricles. Robust automatic contouring with deep learning methods seems viable for local centers with small datasets.The online version contains supplementary material available at 10.1007/s10916-022-01810-6. Cardiac image contouring is an important first step in many diagnostic and radiotherapy planning processes. Quantitative metrics can be extracted by delineating the structures of the heart, i.e., the myocardium, left and right ventricle (LV & RV) and the left and right atrium (LA & RA) Fig. . These cMost automated segmentation methods are based on the use of atlases. Atlas-based segmentation requires long registration times to be accurate . CurrentHowever, deep learning also comes with its own disadvantages, such as the requirement for large datasets and extensive external validation. The European Commission has stated in their proposal for laying down harmonized rules on AI that AI systems should be evaluated on datasets that have appropriate statistical properties regarding the cohorts they are intended to be used on . HoweverThe aim of this project was to develop an automated cardiac contouring pipeline for use in low-dose non-contrast CT scans in local centers with a small dataset with deep learning methods.Our work is part of the development process of an automated coronary artery calcium scoring algorithm . CreatinFifty planning CT scans of patients with breast cancer were selected for this study. These scans contained no clinically relevant abnormalities; the scans were part of radiotherapeutic treatment at the University Medical Center Groningen .The CT examinations were performed with a Somatom Sensation Open CT system , without iodine contrast agent. Field of view was set at 500 mm and 512 × 512 pixels with a thickness of 3 (N = 29) or 5 (N = 21) mm. No interpolation was used to reconstruct the volumes. The CT images were converted to NUMPY format, the contrast was adjusted to the mediastinum window setting . No further pre-processing was done on the images.An experienced cardiac radiologist and physician assistant specialized in breast cancer created manual contours of the whole heart, LV and RV, and LA and RA, based on the atlas of Feng et al.  by generThe dataset was split in 44 training volumes, 3 tuning volumes and 3 internal validation volumes. All 2D slices were extracted from these volumes for the first stage. For the second stage, only the images that contained relevant heart contours were used. We also added 3 slices of liver without heart contours to improve the networks’ recognition of liver areas. The dataset was resplit into 41 training volumes, 3 tuning volumes and 6 internal validation volumes for the second stage by moving 3 3-mm slice thickness patient volumes from the training dataset to the internal validation dataset. The splitting of the dataset was done to get a 50–50 division in the validation volumes between 3 and 5 mm slice thickness scans. An overview of the datasplit is shown in Fig. −4 with Adamax as optimizer.The contouring pipeline consisted of two stages. The first stage was a classifier that classifies axial slices into slices that contain the heart and slices without heart. The architecture was InceptionResNetV2 and is, as the name implies, a hybrid architecture combining the strengths of the Inception and Resnet architectures. This network is 164 layers deep and still trainable thanks to the addition of residual layers in the Inception blocks. The net−3, beta_1 of 0.9, beta_2 of 0.999 and an epsilon of 1e−7 as an optimizer. The loss function used was a hybrid loss of the sum of the dice coefficient loss function and the focal loss function  andThe first classifier for selection of slices containing the heart was very accurate with an accuracy of 99% and an agreement with Cohen’s kappa of 0.98 between the ground truth and the classifier. Table The second stage 2.5D neural networks achieved a median DC of 0.96, 0.88, 0.92, 0.82 and 0.80 for the whole heart, RV, LV, LA and RA contours. 95% HDs were 1.86, 2.98, 2.02, 6.46 and 6.16 mm for the whole heart, RV, LV, LA and RA contours. Volume ratios between the ground truth volumes and the predicted volumes were 0.96, 0.99, 1.05, 0.80 and 0.84 for the whole heart, RV, LV, LA and RA respectively Below is the link to the electronic supplementary material.


TAPSE with the cutoff 19 mm and visual eyeballing significantly predicted survival with HRs of 0.512  and 1.631 , respectively. Conclusions: This large-scale all-comer study confirms that RVF is one of the main drivers of mortality in patients with severe isolated TR. However, the current cut-offs for established echocardiographic parameters did not predict survival. Further studies should investigate the prognostic value of higher thresholds for RVF parameters in these patients.Background: Presence of severe tricuspid regurgitation (TR) has a significant impact on assessment of right ventricular function (RVF) in transthoracic echocardiography (TTE). High trans-valvular pendulous volume leads to backward-unloading of the right ventricle. Consequently, established cut-offs for normal systolic performance may overestimate true systolic RVF. Methods: A retrospective analysis was performed entailing all patients who underwent TTE at our institution between 1 January 2013 and 31 December 2016. Only patients with normal left ventricular systolic function and with no other valvular lesion were included. All recorded loops were re-read by one experienced examiner. Patients without severe TR (defined as vena contracta width ≥7 mm) were excluded. All-cause 2-year mortality was chosen as the end-point. The prognostic value of several RVF parameters was tested. Results: The final cohort consisted of 220 patients, 88/220 (40%) were male. Median age was 69 years (IQR 52–79), all-cause two-year mortality was 29%, median TAPSE was 19 mm (15–22) and median FAC was 42% (30–52). In multivariate analysis, TAPSE with the cutoff 17 mm and FAC with the cutoff 35% revealed non-significant hazard ratios (HR) of 0.75 (95%CI 0.396–1.421,  Evaluation and gradation of right ventricular systolic function (RVF) is an integral part of every transthoracic echocardiographic examination (TTE) ,2,3. CurPresence of high trans-valvular pendulous volume leads to backward-unloading of the ventricle and complicates the functional assessment of the affected ventricle. Established cut-offs for normal systolic performance can overestimate true systolic function, as it has previously been described for left ventricular ejection fraction (LVEF) in the setting of severe mitral regurgitation . TherefoTricuspid regurgitation is a common entity and often occurs as a bystander of other severe cardiac diseases. It is frequently associated with mitral regurgitation, aortic stenosis, and systolic left heart failure, all of them significant drivers of mortality ,9. ThereThe present study sought to evaluate the prognostic value of established cutoffs for several parameters frequently applied to grade RVF in the presence of isolated severe TR.A retrospective analysis was performed entailing all patients who underwent transthoracic echocardiography at our institution between 1 January 2013 and 31 December 2016. Survival was retrieved for 31 December 2018 from the national death registry. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the local ethics committee (EK #1179/2019).The study population consisted of consecutive patients who were graded with TR greater than moderate. All patients with impaired left ventricular systolic function (LVEF < 50%), previous cardiac surgery, congenital heart disease, or any concomitant valvular defect with a severity greater than mild to moderate, as well as repeat examinations were excluded. Subsequently, the remaining patients were classified according to TR vena contracta width (VC). Only patients with severe TR (defined as VC ≥ 7 mm) were included into the final analysis.Echocardiograms were performed using commercially available equipment  according to a standardized protocol by physicians and sonographers blinded to clinical data and outcomes. For this study, all stored loops were re-read by one experienced examiner (AK). Cardiac chamber size and function were assessed according to the recommendations of the European Association of Cardiovascular Imaging using 2D images [The maximal basal RV diameter was measured in an RV focused apical four-chamber view . Size ofComprehensive assessment of TR was performed using vena contracta width (VC), effective regurgitant orifice area (EROA), and regurgitant volume (RegV) using the proximal isovelocity surface area (PISA) method .Visual qualitative quantification of RVF is the most commonly applied parameter in daily clinical practice . Due to In an apical 4-chamber view the maximal systolic excursion of the lateral tricuspid annulus was measured by M-Mode. A TAPSE of <17 mm indicates RV dysfunction .This parameter provides the longitudinal velocity of the tricuspid annular plane by tissue Doppler imaging. The sample volume was placed in the basal segment of the free lateral wall of the right ventricle. An S’ value of 9.5 cm/s indicates RV dysfunction ,3.The endocardial RV boarders were traced during end-diastole (ED) and end-systole (ES) and the respective area was measured. The following formula was applied: 100× (RV-Area ED—RV-Area ES)/RV-Area ED. A value of less than 35% indicates RV systolic dysfunction [Global strain of the free lateral wall of the right ventricle (GLS-RVFW) was calculated by averaging peak systolic strain of the three segments  of the free lateral wall in an RV focused 4-chamber-view. A free-wall-strain of less than −20% indicates reduced RVF .A systematic exploration of the centralized patient management system of Vienna revealed age, sex, and traditional cardiovascular risk factors according to the respective guidelines as previously described . Venous Mortality was analyzed by a retrieval query of the Austrian Death Registry. Record linkage indicated date of death and cause of death encoded according to the International Code of Diseases, Ver. 10 (ICD10). Austrian law demands that all deaths of Austrian citizens  have to be recorded in the central Austrian death registry, which allows an almost complete follow up of all patients .t-test  or with the Mann–Whitney U test . Continuous variables are given as median and interquartile range (Q1–Q3) in the presence of non-normal distribution and with mean ± standard deviation in the presence of normal distribution. Categorical parameters are presented as absolute numbers and percentages.Continuous variables were tested for normal and non-normal distribution by Shapiro-Wilk test. Groups were compared with the Cox proportional hazard regression analysis was applied to assess the effect of RVF on 2-year survival. For TAPSE, S’, FAC, and GLS-RVFW the cutoffs recommended by the current guidelines were applied. To explore possibly better thresholds, a second calculation was performed for each parameter, using the parameter’s median value in this cohort as a cutoff. To account for potential confounding effects, we formed a confounder cluster encompassing age, female sex, creatinine, RA and RV size, and maximal TR velocity (continuous variable).Intraclass correlation coefficient was calculated for 20 randomly selected patients regarding the analyzed RV function parameters.p-values < 0.05 were used to indicate statistical significance. SPSS Version 24  was used for all analyses.Two-sided A total of 36,000 patients received transthoracic echocardiography at our institution between 1 January 2013 and 31 December 2016, 590/36,000 (1.6%) fulfilled the inclusion criteria of severe isolated tricuspid regurgitation  with normal systolic left ventricular function and no other valvular pathology graded as more than mild-to-moderate. We excluded 328 patients due to insufficient image quality, measurements were performed on the remaining 262 patients. Subsequently, 42 patients were excluded due to less than severe TR indicated by a VC < 7 mm .The final cohort consisted of 220 patients, 88/220 (40%) were male. Median age was 69 years (IQR 52–79), median follow-up was 34.5 (18.5–53) months, all-cause two-year mortality was 29% . Cardiovascular comorbidities were coronary artery disease in 28%, diabetes mellitus in 20%, and arterial hypertension in 59% . Additio2 (0.25–0.54), and median regurgitant volume was 44 mL (34–60) , median EROA was 0.4 cm (34–60) .p = 0.034). However, the TAPSE-cutoff of 17 mm did not differentiate between these groups (p = 0.137).The parameter TAPSE was available in 192/220 (87%) of the patients. Median TAPSE was 19 mm (15–22). It was significantly higher in those who survived beyond two years compared to the non-survivors . For the cutoff 19 mm, multivariate analysis revealed a HR of 0.526   of 0.75  , Table 2p = 0.13). The FAC-cutoff of 35% did not differentiate between the two groups (p = 0.56).The parameter FAC was available in 194/220 (88%) of the patients. Median FAC was 42% (30–52). There was no statistically significant difference between the two groups . For the cutoff 42%, multivariate analysis revealed a HR of 0.495   , Table 2p = 0.37).The parameter S’ was available in 153/220 (69%) of the patients. Median S’ was 11 cm/s (8.5–12). There was no statistically significant difference between the two groups . For the cutoff 11 cm/s, multivariate analysis revealed a HR of 1.048   .p = 0.48). For the cutoff −20%, multivariate analysis revealed a HR of 0.338  (The parameter GLS-RVFW was available in 135/220 (61%) of the patients. Median GLS-RVFW was −20% (−11–(−27)). There was no statistically significant difference between the two groups  .p = 0.005). Visual gradation into “normal RVF” and “reduced RVF” showed a significant association with two year survival in multivariate analysis   of the patients were graded as “reduced function”. There were significantly more patients with reduced RVF in the non-survivors when compared to the survivors  .In all analyses, age and creatinine were significantly associated with mortality .p < 0.001) for visual gradation of RV function, 0.92  for TAPSE, 0.99  for S’, 0.87  for FAC, and 0.9  for GLS-RVFW.Interrater variability was tested for 20 randomly selected patients by intraclass correlation coefficient. This was 0.94  showed a significantly better risk discrimination for all-cause two-year survival.Prevalence of isolated severe TR is extremely low. Over the four-years of investigation, of the screened 36,000 patients only 590/36,000 (1.6%) had isolated severe TR. Patients were relatively young with a median age of 69 (IQR 52–79), and prognosis was unfavorable with a 2-year mortality of 29%.Numerous studies have shown that reduced RVF is associated with worse prognosis in severe TR ,16. HoweSevere pendulous volume caused by atrio-ventricular valvular regurgitation leads to hyperdynamic ventricular function in order to maintain sufficient stroke volume. This concept is the reason why an LVEF below 60% is understood to indicate incipient LV dysfunction and therefore is an indication for mitral valve surgery in severe mitral regurgitation . In the Nevertheless, it can be assumed that in severe TR a higher than usual longitudinal and radial function is needed to maintain stroke volume. Our data provides new insights into this matter and challenges the current cutoffs in the presence of severe TR. Neither in univariate nor in multivariable analysis these cutoffs predicted survival. However, when applying higher cutoffs (19 mm in TAPSE), patients with the higher values showed significantly better survival. The same applied for FAC, S’, and GLS-RVFW, however without statistical significance.The presented data were collected from a small number of patients in a single center and may reflect referral bias. The findings therefore indicate that the guideline cutoffs are less reflective of risk in this particular cohort. Consequently, the results can only be hypothesis generating. Future studies should prospectively investigate higher cut-offs for TAPSE, GLS-RVFW, S’, FAC, and RVEF in patients with severe TR.Interestingly, visual estimation of RVF  was able to predict survival in multivariate analysis. This adds to the discussion regarding the optimal parameter for gradation of RVF. TAPSE, GLS-RVFW, and S’ depict longitudinal function of the free lateral wall of the RV, and FAC and RVEF (derived by 3D echocardiography or cardiac magnetic resonance imaging) depict volumetric changes during the cardiac cycle. Visual “eyeballing” by the experienced examiner might be able to give a more holistic estimation of RVF incorporating both longitudinal and volumetric function. This hypothesis is supported by previous data from our group that could show good diagnostic accuracy by eyeballing regarding the differentiation into “normal” and “reduced” RVF .As the right ventricle quickly adapts to changes in volume and pressure, when evaluating patients with severe TR it is important to take into consideration not only parameters of RVF but also pulmonary pressures and right heart dimensions . RecentlIn the analyses performed for this study, the confounders age, RV size, and creatinine contributed significantly to two-year all-cause mortality. Right ventricular size was characterized by basal diameter by our group. Future studies should focus on more comprehensive parameters, particularly indexed 3D end-diastolic RV volume which can be derived in most patients if hardware and software are available . In addiDue to the retrospective design of this study, measurements could only be performed on the available images. This lead to a high drop-out rate due to suboptimal image quality.n = 192/220 (87%), GLS-RVFW n = 135/220 (61%)). This may explain why differences between the lower and higher threshold in S’ and GLS-RVFW did not reach statistical significance. Future studies should investigate these parameters prospectively and in larger cohorts.The investigated parameters were not available for all patients  and systolic dysfunction  were excluded. However, heart failure with preserved ejection fraction (HFpEF) could not be excluded. At the same time, as only patients with isolated TR were analyzed, the reported findings may not be generalized for all patients with TR as most will present with additional left heart disease.TR Vmax measurement was important in this analysis for the assessment of pulmonary pressures. However, in the presence of severe TR, TR Vmax can be false-low despite high pulmonary pressures due to pressure equalization between the RA and the RV. A triangular shaped CW Doppler signal in combination with a low TR Vmax signal is a sign for the presence of pressure equalization. This was present in 13/220 (6%) patients in this cohort.As for mechanism of tricuspid regurgitation, the analyzed patients had functional (secondary) TR, however, there were patients with cardiac implantable electronic devices (CIED). In our clinical experience it is oftentimes not possible to exclude CIED induced TR from retrospective datasets. Therefore, unrecognized patients with primary or structural TR may have been included in the presented data.As the analysis is based on a single center analysis, the results may not generalize to other institutions and there is concomitant referral bias that can influence who receives TTE and mortality rates.This large-scale all-comer study confirms that RVF is one of the main drivers of mortality in patients with severe isolated TR. However, the current cut-offs for established echocardiographic parameters did not predict survival. Further studies should investigate the prognostic value of higher thresholds for RVF parameters in these patients.


The analysis of LV rotational deformation is challenging and requires standardization of image acquisition as well as postprocessing analysis. The aim of this study was to test the feasibility to analyse LV rotational deformation using 2DSTE by introducing a novel algorithm for the detection of artefacts. The study was performed in 20 healthy subjects serving as a control group and in 53 competitive sportsmen. Circumferential, radial strain  and LV rotation were analysed by 2DSTE in parasternal short axis views. The stepwise algorithm to exclude potential artefacts starts with the visual estimation of the image quality with respect to complete visualization of all myocardial segments during the entire cardiac cycle followed by the exclusion of data sets in participants with conduction abnormalities. The next step is the optimization of tracking areas and a cross-check of implausible strain waveforms in multiple acquired comparable cineloops. The last step is the exclusion of strain curves with persisting implausible waveforms if standardization failures and incorrect LV wall tracking are fixed. Plausible physiological strain curves were observed in 89% (n = 65/73) of all subjects. In controls all implausible waveforms could be verified as artefacts. The algorithm was applied in 53 professional athletes to test and confirm its feasibility. Abnormal CS waveforms were documented in 25 athletes, verified as artefacts due to tracking failures in 22 athletes and due to incorrect image acquisition in 3 athletes. CS artefacts were mostly located in the basal posterior and lateral LV segments.  and basal posterior  segments were highly susceptible to artefacts. 2DSTE of parasternal short axis views to analyse circumferential and radial deformation as well as LV rotation is feasible in athletes. The proposed algorithm helps to avoid artefacts and might contribute to standardization of this technique. 2DSTE might provide an interesting diagnostic tool for the detection of viral myocarditis, e.g. in athletes.The online version contains supplementary material available at 10.1007/s10554-021-02213-3. Over the past decade, the analysis of longitudinal deformation by 2D speckle tracking echocardiography (2DSTE) is established for the assessment of global and regional left ventricular (LV) systolic function with low interobserver variability , 2. ThisThe main problem of analyzing myocardial mechanics by RS, CS, and LV rotation using 2DSTE is still the necessity of a standard operation procedure for image acquisition and defining tracking areas , 13. SucThe different LV layers contribute to radial contraction by different components of LV deformation. The architecture of the LV myocardial fibers shows longitudinal fibres located predominantly within the inner LV layers and circumferential fibres located predominantly within the outer LV layers, respectively , 16. TheThe analysis of LV wall motion includes different components of LV rotational deformation Fig. . StandarOptimal parasternal acoustic windows and adequate image quality are of tremendous importance to assess RS, CS an LV rotation by 2DSTE. Consequently, this method of LV strain analysis is preserved for patients, where standardized parasternal image acquisition is possible with adequate image quality. Thus, this 2D technique is predominantly suited for younger, normal weight subjects, e.g. athletes, and patients without obesity and/or pulmonary diseases. The feasibility of 2DSTE, however, should be proven for the analysis of RS, CS, and LV rotation, which might be presumably important for the detection of myocardial involvement in acute myocarditis, which predominantly affects the outer LV layers being responsible for the rotational LV motion –25. To eConsequently, the present study focuses (1) on the methodological prerequisites for establishing the analysis of LV rotational deformation in cohorts with adequate parasternal acoustic window and (2) on an algorithm to differentiate pathological findings from artifacts analyzing parasternal short axis views by 2DSTE. Thirdly (3), the feasibility of this approach was tested in a cohort of athletes with the intention to illustrate a new diagnostic option for the detection of myocarditis by echocardiography. The verification of pathological findings and the delineation of pathologies from imaging artifacts are described by a detailed proposed algorithm. The necessity of an adequate acoustic window obviously provides limitations of the described 2DSTE approach. However, the analysis of LV rotational deformation might be helpful in cohorts with normal cardiac geometry, in which adequate image quality of parasternal short axis views is present to detect potential acute myocarditis in future clinical practice.A total of 83 healthy participants  were screened. 5 controls and 2 athletes had to be excluded from the data analysis due to bad parasternal image quality and 3 athletes were excluded due to complete right bundle branch block with regional wall motion abnormalities  by two experienced physicians at the University Hospital of Leipzig between June 2019 and May 2020. However, only one echocardiographic investigation was performed in each participant. Prerequisite was generally the documentation of the complete LV wall during the entire cardiac cycle with an optimal image quality of the parasternal short axis views. The short axis views were exactly adjusted perpendicular to the long axis view by previous biplane scanning to avoid oblique LV scanning. In addition, the basal, mid, and apical short axis views were verifiably matched to the respective LV levels of a standardized long axis view by biplane LV scanning and by corresponding apical LV views to enable analysis of LV rotation, twist, and untwisting in relation to maximum end-diastolic and end-systolic LV length. For each sectional plane  at least two different loops were recorded to enable a comparison of 2DSTE analysis by postprocessing between the respective cineloops to detect possible contact artefacts between transducer and skin, or artefacts due to rib or lung shadowing.Deformation parameters of RS, CS, and LV rotation were assessed by Quantitative Analysis . The tracking areas were placed manually at the epicardial and endocardial contour of the LV wall with at least three different region of interest (ROI) widths for each section. Data were analysed by quantitative assessment of the respective strain graphs.RS curves show positive monophasic waveforms during systole with a peak maximum at end systole prior to or at aortic valve closure (AVC) reflecting myocardial wall thickness . Pathological findings are observed in case of maximum RS values after AVC , no significant RS increase or even RS decrease during systole, or dispersion of regional RS curves with maximum values < 25% of the highest maximum value.CS curves show negative monophasic waveforms during systole with a minimum peak at end systole prior to or at AVC reflecting circumferential shortening . Pathological findings are observed in case of minimum CS values after AVC , no significant CS decrease or even CS increase during systole, or dispersion of regional circumferential strain curves with minimum values > 25% of the lowest minimum value.Circumferential layer strain normally shows a homogeneous gradient  between subendo- and subepicardial strain. Thus, normal CS layer strain is characterized by a homogeneous pattern of reduced subepicardial CS peak values as well as waveformes with lower minimum values in comparison to the subendocardial CS. Pathological findings might be observed if no gradient between subendo- and subepicardial strain, or positive CS values are present .Basal LV segments rotate clockwise and present a mean rotation of more than − 3° reaching the minimum prior to or at AVC, which corresponds to the mean value of basal LV rotation minus one standard deviation (SD)  and untwisting (diastole)  , 12. NorNormal net rotation rate is qualitatively characterized by a biphasic shape and by crossing the zero-line prior to or at AVC. During diastole only minimum excursions near the zero-line are normal.The sequence of the proposed algorithm started with the visual estimation of the image quality with respect to complete visualization of all LV segments. If the LV myocardium of the respective short axis views was not completely visualised during the entire cardiac cycle, images were not accepted, and analysis by 2DSTE is not possible. The next step contained the analysis of strain curves with respect to plausible physiological patterns. Normal waveforms and patterns of RS, CS, and LV rotation curves as well as normal values were defined by the following –9:RS curIf strain waveforms are not normal after tracking analysis by user-independent automated area tracking, the width of the tracking area was adjusted for full myocardial tracking of the LV wall. In a first step, the tracking width was uniformly changed. In a second step, the regional contours of the tracking area were manually corrected within each LV segment.If the complete LV wall is visualized in all segments of the 2D parasternal short axis views, artefacts might be induced by pronounced echo-dense epicardial contours due to paracardial fibrous tissue—especially in the anterior, lateral, and posterior segments—or rib shadowing and lung superimpositions. With respect to these structures, the tracking width was manually adjusted to the width of the respective regional LV myocardium to optimize tracking quality. If strain curves normalize after this postprocessing manoeuvre, the previously abnormal waveforms is presumably an artefact.The analysis of apical rotation was of particular importance. The counter-clockwise rotation of the LV apex is only detectable, if the sectional plane is really within LV regions near the LV apex. The apical LV level of a short axis view can be documented by biplane scanning directly prior to the acquisition of the respective 2D short axis views. The acquired apical sectional plane should be within the apical third of the LV long axis during end systole to ensure the correct visualisation of rotational LV deformation. In addition, biplane scanning is helpful to detect parts of the aortic root, the coronary sinus or the left atrium, if scanning of the basal short axis view is too caudal and not perpendicular to the LV long axis.If pathologic waveforms are still present after these sequences of the algorithm, all these manoeuvres should be applied in additionally acquired cineloops.Findings of adjacent LV regions should be interpreted with respect to the plausibility of pathological findings, e. g. if suspicious findings of mid LV segments can also be documented in the corresponding apical or basal segments, the suspicious findings are highly susceptible for pathological entities.The reproducibility of pathologic waveforms after passing through this algorithm should be checked in all additionally acquired loops of the same sectional plane.Deviations of strain waveforms from the described characteristics are present in some cardiac diseases or in case of artefacts showing chaotic/noisy patterns. For the differentiation between artefacts and pathological findings, we propose the third step of the algorithm starting with a second thoroughly reviewing of the short-axis images with respect to standardization failures followed by manual adjustment of the tracking areas to exclude tracking of non-myocardial structures Fig. .If straiAll statistical analyses to compare mean values of the alphanumeric data between controls and athletes were performed using SPSS version 24.0 . Group difference verification was performed using the Mann–Whitney U test. A p value < 0.05 was considered to indicate statistical significance. Inter-observer variability of all presented parameters was assessed in ten randomly selected controls and ten athletes, respectively, by two experienced investigators using the same datasets blinded to each other’s results as performed in previous studies .Mean values for RS, CS, and LV rotation after adjusting the tracking area to avoid artefacts determined in healthy volunteers and athletes are presented in Table CS abnormal strain waveforms was most frequently observed. In 6 of 20 controls and in 25 of the athletes abnormal CS findings were present , basal posterior , apical lateral, apical posterior, and apical inferior LV segment  using automated tracking areas without manual correction . However, pathological CS waveforms were still observed in the basal lateral and basal posterior LV segment . All these pathological CS waveforms could be allocated to artefacts due to scanning of structures beside the LV wall, which were caused by inadequate sectional planes. No pathological waveforms have been documented in the apical LV segments after following the proposed algorithm  were below this range in the present study . The dispersion of regional LV rotation often varying with changing width of the tracking area, whereas the corresponding mean value of LV rotation and the waveform of global LV rotation remained in the same range  in cardiac magnetic resonance tomography (CMR) . Thus, tThe main diagnostic problem—especially in patients with acute myocarditis—is the regional correlation of CS artefacts with definite pathological findings of LE, which is most frequently seen in the basal posterior and lateral segments in CMR studies. Thus, the differentiation of 2DSTE artefacts from pathological findings is important and can only be solved by an accurate methodologic approach.The present study was performed in healthy volunteers and in athletes who often have a good parasternal acoustic window. Thus, these cohorts do generally not represent the image quality of patients with cardiac diseases, in whom lung diseases, obesity and multiple other reasons cause limitations of image quality. However, with respect to the potential detection of myocarditis these cohorts are of particular interest for echocardiographic screening. It should be accentuated that the current study does not validate this algorithm to differentiate between athlete's heart and cardiomyopathies. This algorithm only provides a methodological guide to verify artefact detection by checking the strain waveforms with respect to plausibility. If 2DSTE of parasternal short axis views fails due to bad image quality, perhaps 3D strain analysis of 3D data sets with high image quality is fundamentally able to overcome the limitations of 2D TTE, but in comparison to 2D TTE, spatial and temporal resolution of 3D TTE is lower. So far, 3D STE is rarely tested—especially for the assessment of CS, RS and LV rotation , 49.The proposed algorithm seems to facilitate the differentiation between pathological strain and artifacts. 2DSTE of parasternal views might be a useful method to quantify RS, CS, and LV rotation. The prerequisites to apply this technique are the acquisition of representative standardized views and the full LV myocardial tracking excluding valvular or paraventricular structures. Biplane scanning is useful to verifiably document short axis views perpendicular to the LV long axis view, and to exclude oblique short axis views as well as artefacts due to paraventricular structures.The proposed algorithm for analysis of LV rotational deformation by 2DSTE helps to avoid artefacts with respect to the interpretation of deviant strain waveforms and might contribute to a standardization of this technique and will encourage the use of 2DSTE in the clinical scenario- The present study showed that the algorithm is feasible in healthy volunteers and athletes with adequate parasternal image quality. Thus, 2DSTE might provide an interesting diagnostic tool for the detection of viral myocarditis in athletes and in patients with an adequate parasternal image quality—especially at stages with normal or preserved LV ejection fraction.Supplementary file1 (TIF 2251 kb)Supplementary file2 (TIF 2147 kb)Supplementary file3 (TIF 457 kb)Supplementary file4 (TIF 836 kb)Supplementary file5 (TIF 2407 kb)Supplementary file6 (TIF 1228 kb)Supplementary file7 (DOCX 53 kb)Supplementary file8 (DOCX 14 kb)Below is the link to the electronic supplementary material.


Pulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension.Pulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2–3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilising period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test.p = 0.04), lower cardiac index (− 23% p = 0.04), lower systolic blood pressure  and reduced left ventricular end-diastolic volume . When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p < 0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p < 0.05) in pulmonary artery-banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery-banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p < 0.05) and diastolic arterial pressure (p < 0.05).At baseline, pulmonary artery-banded animals had increased right ventricular pressure (+ 39%, While norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume. Patients with pulmonary hypertension have a sevenfold increased 1-year standardised mortality ratio and are hospitalised with greater frequency –5, 7, anWith disease progression, the increased pressure in the right ventricle will compress the left ventricle by leftwards deviation of the interventricular septum, hence decreasing left ventricular filling and compromising diastolic , 9 and sThe choice of perioperative inotropic support or vasopressors for these patients is disputed and relies on limited data. Norepinephrine, dopamine, adrenaline, dobutamine, levosimendan and milrinone have all been suggested and used , 11, 12.The ideal treatment for the stabilisation of the chronically pressure-overloaded failing right ventricle in the perioperative environment involves increasing systemic pressure, improving myocardial perfusion, increasing biventricular myocardial contractility and stroke volumes while avoiding increases in pulmonary artery resistance. In the failing right ventricle, the treatment effect is summarised by the ratio of pulmonary artery elastance and the right ventricular contractility also known as the arterio-ventricular relationship of the failing right ventricle.1-adrenergic receptor agonist with low β-agonist activity, and therefore a powerful vasoconstrictor. It has only direct inotropic properties at high doses. Dobutamine is a synthetic catecholamine with a strong affinity for both β1- and β2-receptors and low α1-adrenergic agonism. The combined effect is most often mild vasodilation at lower doses and strong inotropic effect at higher doses.With this in mind, we undertook an experimental animal study of pressure-overloaded right ventricular failure and studied the effects of norepinephrine and dobutamine, as they have distinctly different haemodynamic effects. Norepinephrine is a potent αWe chose a model of moderate pulmonary hypertension, as this group is much more likely to undergo general anaesthesia and pressure overload ventilation when compared to patients with severe pulmonary arterial hypertension, in which case regional anaesthesia would be preferred. Clinically relevant dosages of norepinephrine and dobutamine were used, and haemodynamics and arterio-ventricular coupling, measured by the conductance catheter technique were chosen as the main endpoints.This study was conducted in conformance to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health  and the n = 5). The pulmonary artery was exposed through a left lateral thoracotomy. Growth-induced stenosis was created by fitting two silicone bands around the pulmonary artery, as described in a previous study [n = 6).Danish landrace piglets aged 2–3 weeks (≈ 8 kg) underwent surgical pulmonary artery banding  every 30 min to ensure normal ventilation and oxygenation. Lactate levels were also analysed. Body temperature was maintained within the normal range (38–39 °C) using a warming blanket. Continuous analgesia and anaesthesia were maintained with Fentanyl (25 μg/kg/h) and Sevoflurane inhalation at 2.7%. Prior to surgery, the animals were administered prophylactic antibiotics  and analgesics (Flunixin 25 mg), both as intramuscular injections. Following the surgery, the animals were aroused and extubated when they started moving and breathing steadily on their own.The animals were pre-medicated immediately upon arrival at the surgical facilities with midazolam (0.5 mg/kg) and azaperone (0.5 mg/kg), to allow for the establishment of intravenous access. Propofol (3 mg/kg) and pancuronium (0.1 mg/kg) were administered to allow endotracheal intubation. The animals were ventilated  with a tidal volume of approximately 10 mL/kg, a fraction of inspiratory oxygen of 35% and a positive end-expiratory pressure of 4 cm HOver the following 5 days, veterinary technicians administered the animals with Flunixin 25 mg and penicillin (100.000 IU) once daily and paracetamol 250 mg  orally twice daily.On the day of re-examination, the animals were anaesthetised and ventilated using the same protocol but omitting pancuronium. Four sheaths were inserted bilaterally into the jugular veins and carotid arteries of the animals. They were then administered 150 IU/kg of heparin prior to catheter insertion, to avoid clotting within the sheaths. Following the administration of 500 μg fentanyl euthanasia was performed by excision of the heart.2, %). Mean arterial pressure , mean pulmonary artery pressure (mPAP) and central venous pressure  were measured at the level of the phlebostatic axis and recorded continuously using pressure transducers  throughout the experiment. Heart rate  was determined from the arterial pressure curve.A Swan-Ganz catheter  was inserted into the pulmonary artery to continuously determine cardiac output (CO) and mixed venous oxygen saturation , preload recruitable stroke work , end-systolic pressure–volume relationship , end-systolic pressure–volume relationship x-axis intercept  and maximum ventricular pressure  were used as measures of systolic function. The end-diastolic pressure–volume relationship  was used as a parameter for ventricular stiffness, and the isovolumic relaxation constant (Weiss method)  was employed as a parameter for active diastolic relaxation. Arterial elastance (Ea mmHg ml−1), a measure of the arterial load, was calculated as the ventricular end-systolic pressure (mmHg) divided by the stroke volume (ml) and calculated for both ventricles. The arterio-ventricular coupling was defined as ESPVR divided by Ea. Signals were sampled using an MPVS Ultra , processed in PowerLab 16/35 , recorded at 2 kHz and analysed in LabChart 7 Pro .The maximum rate of pressure change (d5/kg) and the pulmonary vascular resistance index  were calculated as 80 (MAP – CVP)/CO/kg and 80 (right ventricular mean pressure – left ventricular minimum pressure (Pmin))/CO/kg, respectively. CO, stroke volume (SV) and ventricular volumes were indexed to body surface area  [The systemic vascular resistance index  .g at 2–8 °C. The plasma was stored at − 80 °C. All samples were thawed and analysed at the same time. NT-proBNP was assessed using an ELISA KIT .Venous blood was sampled at 16 weeks, following pulmonary artery banding. Lithium–heparin-coated vacutainers were used for sampling and centrifuged for 15 min at 1000×−1) or dobutamine . Each step was performed for 10 min and concluded with new measurements. After a washout period of 30 min, new baseline measurements were taken and the second treatment was started in incremental steps  were conducted to achieve approximately 100% increase in contractility, estimated by PRSW for both norepinephrine and dobutamine.Following instrumentation, the animals were subjected to a 30-min stabilisation period, after which baseline measurements were taken. The animals were then randomised to start incremental intravenous infusions with either norepinephrine . Significant differences were assessed using a two-tailed Student’s p-value of 0.05 was considered to be statistically significant.The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA (between-group differences) and Bonferroni multiple comparisons post-test, using the GraphPad Prism 5.04 software . If significant difference was detected between baseline and post-washout, the data were analysed as relative changes from baseline. A p = 0.04) due to lower SV . SVRI and left ventricle (LV) Ea were equal between PAB animals and controls. However, a significantly low SAP  was observed in PAB animals. Pulmonary resistance was significantly higher in the PAB animals when compared to the controls, as assessed with both PVRI  and right ventricular (RV) Ea .No differences were found between the two groups in terms of animal age, weight and BSA Table . CI was Pmax , RV Pmean , RV ESPVR , and RV dP/dtmax  (Table p = 0.1). The atrioventricular relationship was not significantly changed (p = 0.1) and RV EF was maintained (p = 1.0). Diastolic properties were unchanged in both active (RV Tau p = 0.9) and passive ventricular relaxation .In the PAB animals, the RV had significantly increased ejective force, as shown by greater RV Pmax , EDV  and ESV  were lower and LV EF  was significantly higher in the PAB animals when compared to the controls. LV PRSW, LV ESPVR and LV dP/dtmax were unchanged between the two groups (p > 0.05). Of the diastolic parameters, only Tau was significantly different between the two groups.In the LV, NT-proBNP concentrations were significantly higher in the PAB animals when compared to the controls, as were arterial lactate levels Table .p > 0.05). However, a significantly greater CI was observed in norepinephrine-treated controls, at the highest infusion concentrations (p < 0.05 and p < 0.01), respectively  and DAP  when compared to dobutamine in PAB animals, but had equal effects on SAP (p > 0.05). In controls, norepinephrine increased SAP (p < 0.01) and DAP (p < 0.05) significantly more than dobutamine, but no difference was found in MAP (p > 0.05) . SVRI decreased in both groups with increasing doses (p < 0.0001), but no differences were found between the treatment groups in both PAB and control animals (p > 0.05). PVRI did not change with increasing doses of norepinephrine or dobutamine in both PAB and control animals (p > 0.05)  Fig. . Dobutam05) Fig. .p < 0.05) and Pmax (p < 0.001), but no difference was observed in ESPVR. No difference in LV contractility was observed in controls. LV EDV decreased with increasing doses in both treatment groups. However, LV EDV was significantly higher during norepinephrine treatment compared to dobutamine (p < 0.05)  in the right ventricle and increased RV systolic pressures  to the same level. RV Ea/ESPVR was improved significantly more by dobutamine  in PAB animals compared to Norepinephrine (− 4%), while there were no differences in LV Ea/ESPVR  did not change with increasing infusion rates in any of the groups (p < 0.05)  Fig. . Norepinphrine − %, while  Fig. . Np < 0.05), but without any differences between the groups . Also, the end-diastolic volume was found to be significantly higher during norepinephrine treatment. Logical conclusions can be drawn to justify the differences between the results of the two studies. In chronic pressure overload of the right ventricle, gradual muscular development was induced to compensate for the increase of right ventricle afterload. With right ventricle systolic function relatively well-preserved, the relative effect of dobutamine will be minor and therefore not remedy the effect of the reduced left ventricle end-diastolic volume.The optimal circulatory perioperative management of patients with pulmonary hypertension is focused on increasing or maintaining the mPAP and PVRI/SVRI ratio, thereby normalising the interventricular septum displacement and improving the arterio-ventricular coupling of the right ventricle. Research data conforming to large animal models with chronic pulmonary artery hypertension on the topic of inotropic support is scarce. In an experimental model of acute right ventricular pressure overload failure, Kerbaul et al.  found thThough systemic vascular resistance index was not statistically greater in the norepinephrine group, the greater afterload was enough to improve left ventricle ejection force by normalising the geometry of the left ventricle and improving systolic and diastolic function in accordance with the literature , 13, 22.At the baseline, systemic pressures were significantly lower in the banded animals. In the perioperative setting, a treatment to counterweight the hypotensive effect of general anaesthesia will be required, and as such dobutamine was found to be ineffective. This point is especially important for centres that use inodilators such as milrinone and levosimendan in combination with a pressor/inotrope during stabilisation of these patients .Diastolic active relaxation was significantly reduced in banded animals, in accordance with general literature and our own previous findings , 24. ThiPassive relaxation (EDPVR) did not differ between controls and banded animals and was unaffected when the doses of dobutamine and norepinephrine were increased. The preserved passive relaxation points to an unaltered extracellular matrix and no fibrosis. This would be consistent with previous studies, wherein no or little fibrosis was found , 25, 26 This study underlines the importance of a thorough pre- and perioperative assessment in this patient group. In patients with pulmonary hypertension and reduced left ventricular end-diastolic volume, deterioration of haemodynamics must be expected during induction of anaesthesia and positive pressure ventilation. Albeit increasing heart rate and thereby reducing filling time, norepinephrine kept the left ventricular end-diastolic volume constant, essentially at net increase. In a previous study that used the same model as the present study , we founAlthough this study has used a model of pulmonary artery constriction over a timespan longer than that used in any previous study, the degree of resemblance to patients with pulmonary hypertension is uncertain. We did not investigate myocardial fibrosis or intracellular changes as is observed in advanced heart failure .When exposing pigs to chronic pressure overload pulmonary hypertension to general anaesthesia and positive pressure ventilation, we found that norepinephrine and dobutamine had the same positive effect on cardiac output, although achieved in distinctly different manners. Dobutamine improved the right ventricular arterio-ventricular coupling, while norepinephrine produced greater left ventricular contractility by improving the placement of the interventricular septum, and therefore increasing the end-diastolic volume of the left ventricle. Further, in the norepinephrine-treated animals, the improvement in cardiac index was accompanied by significantly greater systemic blood pressures.


To study the outcomes of a novel modified pulmonary artery banding (mPAB) technique used for staged repair of a subset of patients with complex transposition physiology.A total of 13 patients who underwent mPAB during their staged repair  or palliation  from 2004 to 2020 were studied retrospectively. A restrictive interposition graft was used to reconstruct the main PA between the pulmonary root and the distal pulmonary confluence, functioning as a mPAB. Twelve of the 13 patients (92.3%) underwent a concurrent arterial switch operation (ASO), of which 6 were palliative ASOs for 1-1/2 repair (n = 1) or UVR (n = 5). Patient weight and cardiac anatomy determined the size of interposition graft.The disease spectrum included dextro transposition of the great arteries (d-TGA) with multiple ventricular septal defects (VSDs) (n = 4), Taussig–Bing anomaly (n = 3), d-TGA with VSD and hypoplastic right ventricle (RV) (n = 3), double-inlet left ventricle with l-TGA (n = 2), and congenitally corrected TGA with double-outlet RV (n = 1). The Lecompte procedure was performed in 10 patients. Predischarge echocardiography revealed a band gradient of 61 mm Hg  for BVR/1-1/2 ventricular repair (n = 7) and 49 mm Hg  for UVR (n = 6). Survival was 100% at a median follow-up of 3.7 years .The mPAB technique is effective and reproducible for staged BVR or UVR for patients with TGA. It effectively regulates pulmonary blood flow, may reduce neopulmonary root distortion, and eliminates complications associated with band migration in standard PAB.  See Commentaries on pages 121, 124, and 126.The novel technique of modified pulmonary artery banding (PAB) effectively restricts pulmonary blood flow with transposition physiology after an arterial switch operation while avoiding complications of standard PAB.Modified pulmonary artery banding (PAB) when performed in transposed great vessel physiology following a definitive or palliative arterial switch operation (ASO) functions better with both the diameter and the length of the interposition graft contributing to restriction of pulmonary blood flow. It eliminates the possibility of band migration associated with standard PAB and may reduce neopulmonary root distortion after ASO.Pulmonary artery banding (PAB) is a palliative cardiac surgical technique used as an interim approach for the surgical management of a range of congenital heart defects associated with excessive pulmonary blood flow. Since its introduction,,One such indication is the presence of multiple ventricular septal defects (VSDs) with dextro transposition of the great arteries (d-TGA).In this study, we evaluated the indications, technical aspects and outcomes of mPAB since its inception at our institution for patients with transposition physiology who required either univentricular palliation or staged biventricular repair (BVR).Between August 2004 and June 2020, 13 patients with transposition anatomy combined with VSD(s) or single ventricle physiology producing unrestrictive pulmonary blood flow underwent mPAB to restrict pulmonary overcirculation at the Children's Hospital at Westmead. Patients were retrospectively identified from institutional cardiac surgical databases, and the study was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee (reference no. 2020/ETH01912). The need for informed consent was waived.Neonates were stabilized in the neonatal intensive care unit, and mPAB was performed, with concurrent definitive or palliative ASO in all but 1 case. Interposition graft length was measured by reviewing postoperative imaging .A), and the arch was then reconstructed using the interdigitating techniqueA and B).Through a median sternotomy, standard cardiopulmonary bypass was established under systemic heparinization, and coronary transfer with aortic reconstruction was performed following routine steps. For concomitant aortic arch repair, innominate artery cannulation was performed with a polytetrafluoroethylene (PTFE) side graft , A, and C).The Lecompte maneuver was performed selectively, the ascending aorta was anastomosed to the neoaortic root, and the defects in the facing sinuses of the neopulmonary root were reconstructed with autologous pericardial patches. Pulmonary arterial continuity was then reestablished using the mPAB technique , C.B and C). In 1 patient, the neopulmonary root was too large for this technique, so a homograft patch was first sutured to close it. Then a central fenestration of 5 mm was created into the patch, and the PTFE graft was then anastomosed to this fenestration. In another patient (as demonstrated in D and E). The diameter and length of the interposition graft were tailored to the each patient's weight and underlying anatomy.A suitably sized PTFE tube graft was anastomosed end-to-end to the reconstructed neopulmonary root, thereby gathering the sinotubular junction of the neopulmonary root onto the much smaller PTFE graft. This required a significant amount of nearing and faring of sutures to compensate for the size mismatch , B and CThere were two patients in whom mPAB was performed following delayed presentation of single ventricle physiology. The first patient had d-TGA, a hypoplastic RV, and a large inlet VSD with a straddling atrioventricular valve not amenable to biventricular repair (BVR). The patient had been initially palliated at another institution with traditional PAB via left thoracotomy but had persistently elevated pulmonary vascular resistance, contraindicating single ventricle palliation with a venous shunt. At 1 year of age, he underwent a palliative ASO with mPAB, atrial septectomy, and open lung biopsy at our institution to manage unfavorable transposition streaming and better restrict pulmonary blood flow to remodel the pulmonary vascular bed. He ultimately proceeded to successful staged completion of total cavopulmonary connection.The second patient had a double-inlet left ventricle with l-TGA. He presented late at age 6 years with pulmonary hypertension but dynamic pulmonary vascular resistance and so underwent traditional PAB as an initial palliation, followed by bidirectional Glenn shunt (BDGS) with mPAB to further restrict antegrade pulmonary blood flow as stage II palliation and then extracardiac Fontan completion as stage III palliation.Redo sternotomy and closure of VSD(s) was done in standard fashion using cardiopulmonary bypass. The interposition PTFE tube graft and previously placed patch at the pulmonary confluence were then completely excised. Vertical incisions were made into each pulmonary valve sinus across the restricted sinotubular junction. Each of these sinuses was then augmented with a patch of autologous/bovine pericardium sutured in place to reconstruct a normal-sized pulmonary root, which was then anastomosed to the distal pulmonary confluence. After weaning from cardiopulmonary bypass, direct RV and PA pressures were measured to define any residual gradients.This patient had d-TGA, moderate RV hypoplasia, a large muscular VSD, aortic coarctation, and arch hypoplasia and had undergone initial ASO with mPAB and concomitant aortic arch repair. At stage II, the VSD and the atrial septal defect were closed, and the pulmonary root was reconstructed as described above. A right-sided BDGS was then constructed in a standard fashion along with bovine pericardial patch augmentation of a hypoplastic right PA (RPA).Debanding and interruption of antegrade pulmonary blood flow was undertaken at either stage II (BDGS) or stage III (completion Fontan) palliation. The debanding was always carried out under aortic cross-clamping because of the univentricular anatomy. The interposition graft was removed from the distal anastomosis, and the opening in the pulmonary confluence was closed either directly or using a bovine pericardial patch. The proximal end of the graft was removed, the pulmonary valve cusps were excised, and the pulmonary root was closed directly.Data are presented as median and interquartile range (IQR) unless stated otherwise.The spectrum of morphologic diagnoses included d-TGA and multiple VSDs (n = 4); Taussig–Bing anomaly (n = 3); d-TGA, VSD, and hypoplastic RV (n = 3); double-inlet left ventricle with l-TGA (n = 2); and congenitally corrected TGA with double-outlet RV (n = 1) . A totalPreoperative patient demographics are summarized in z-score of neopulmonary annulus size for BVR/1-1/2 ventricular repair (n = 7) was −1.03 (IQR −1.24 to 0.46), and that for UVR (n = 4) was −2.46 . Patients K and M were excluded from these analyses because they were older and presented to our institution later than the other patients in the study cohort. Intraoperative and postoperative demographics are detailed in The median size of the interposition graft used was 4.0 mm , and the median length was 8.0 mm . Indexing interposition graft diameter to patient weight revealed a median ratio of 1.35 mm/kg  for patients undergoing BVR/1-1/2 ventricular repair (n = 7) and 1.35 mm/kg  for those undergoing UVR (n = 4). The median length of the grafts used for BVR/1-1/2 ventricular repair (n = 7) was 3 mm , whereas that for UVR (n = 4) was 13 mm . Indexing graft length to patient weight at the time of surgery for those undergoing neonatal procedures revealed a median ratio of 1 mm/kg  for BVR/1-1/2 ventricular repair (n = 7) and 4 mm/kg  for UVR (n = 4). The median The most common postoperative complications seen were low cardiac output state (n = 10), renal dysfunction requiring peritoneal dialysis (n = 4), and cardiac arrhythmias (n = 4) . PrediscAll patients had planned reinterventions, and total reinterventions  are summarized in The patient who underwent 1-1/2 ventricle repair (patient G) had a straightforward stage II procedure involving PA debanding and reconstruction, VSD closure, atrial septal defect closure, RPA augmentation, and BDGS anastomosis. Of those who underwent univentricular palliation (n = 6), the first reintervention involved BDGS (n = 4), branch PA augmentation (n = 1 LPA and n = 1 RPA), PA interruption (n = 2), and completion Fontan (n = 2). The second reintervention involved PA interruption followed by BDGS (n = 1), LPA stenting (n = 1), or completion Fontan (n = 1). One patient underwent completion Fontan along with LPA stenting as a hybrid procedure, and another patient underwent fenestrated Fontan as a third reintervention.Patients C, E, and I had eventful recoveries following mPAB and required unplanned subsequent reinterventions . While aPatient C had failed attempts at extubation following the debanding and PA reconstruction procedure. Cardiac catheterization study revealed an aortopulmonary collateral and a potentially significant muscular VSD. The collateral was occluded with a coil, and device closure of the VSD was attempted, which caused iatrogenic VSD enlargement. The patient then underwent bilateral branch PAB for stabilization as a second reintervention, followed by VSD device closure with branch PA reconstruction 1 year later.Patient M required a post-Fontan subaortic myectomy with anterior enlargement of the VSD for progressive development of subaortic stenosis in the context of double-inlet left ventricle and l-TGA.All patients were alive and well at the time of this report, at a median follow-up of 3.7 years . The most recent echocardiography studies for all patients who underwent BVR (n = 6) showed no neopulmonary regurgitation in 2 patients and trivial to mild regurgitation in the other 4 patients. Three patients had no RV outflow tract obstruction, whereas the other 3 had RV outflow tract peak gradients of 12, 16, and 39 mm Hg.The last decade has seen an increasing preference for early complete primary repair of complex congenital cardiac defects rather than staged repair with interim palliation. However, in some situations, anatomic complexity associated with a technically challenging repair favors a staged approach to provide physiologic stability and facilitate somatic growth to achieve a final successful definitive repair. In univentricular physiology with unrestricted pulmonary blood flow, transposition streaming limits the ability to achieve adequate restriction of pulmonary blood flow with traditional PAB owing to the consequent cyanosis. In these cases, it may be preferable to correct transposition streaming with a palliative ASO to enable adequate restriction of antegrade pulmonary blood flow.We have found this technique to be particularly useful in the context of a palliative ASO to predictably regulate antegrade pulmonary blood flow rather than relying on native neopulmonary valvar or subvalvar obstruction, which can be dynamic and variable. mPAB is also useful for late-presenting univentricular anatomy with unrestricted pulmonary blood flow necessitating PAB as initial palliation. The main PA is very large and tense in this context, making it challenging to achieve adequate constriction and risking vascular injury with traditional PAB. There is probably less distortion of the neopulmonary valve and neopulmonary root with mPAB, because this technique avoids the infolding of the pulmonary arterial wall that can occur with standard external PAB. Complications inherent to traditional PAB, including distal band migration with compression of branch pulmonary arteries, proximal band migration with distortion of the neopulmonary valve, and coronary artery compression, are impossible with mPAB owing to the fixed placement of the interposition graft. The PTFE material used for banding (both standard and modified) inevitably incites scarring and adhesion formation; however, mPAB is advantageous, in that the band does not require removal from underlying structures but is simply excised.In 1972, Truslerp = 8μLQ/πR4,p) through a cylindrical tube is directly proportional to the length of the tube (L) and the volumetric flow rate of an incompressible fluid (Q) through the tube, but inversely proportional to the fourth power of radius of the tube (R). Consequently, the diameter (or radius) at the banded site is the most important determinant of band gradient regardless of the technique used. Intraluminal PAB also has been used in similar clinical situations,The major difference in flow dynamics with mPAB versus traditional PAB is best explained by the Hagen–Poiseuille equation, ΔThe goal for patients in our cohort with d- or l-TGA, single ventricle anatomy, and unrestricted pulmonary blood flow was to achieve unobstructed systemic outflow with aortic arch augmentation when required, correct transposition streaming and systemic outflow tract obstruction with palliative ASO, and then control the pulmonary blood flow with mPAB to enable staged Fontan palliation. In the 1 patient who did not undergo palliative ASO with mPAB (patient M), unfortunately, the pulmonary valve was sacrificed at Fontan completion rather than debanding and incorporating it into a Damus–Kaye–Stansel anastomosis. He later required subaortic resection. Importantly, mPAB facilitates long-term preservation of the pulmonary valve, particularly with downsizing of the interposition graft at interim stages to enable late incorporation in to a Damus–Kaye–Stansel anastomosis when required. All other patients had d-TGA with multiple VSDs, making complete primary repair challenging and the likelihood of residual defects high. We opted to use mPAB with ASO in this group to restrict left-to-right shunting and to allow spontaneous closure of small VSDs. Persistent large defects were then closed at a later stage with acceptable surgical/interventional risk with concurrent BDGS in the context of RV hypoplasia (n = 1).After indexing the diameter of interposition graft to the weight of the patient, an identical ratio was obtained for BVR versus UVR; however, the graft was longer for univentricular conditions . This caThis study was retrospective in nature and subject to the limitations inherent to observational investigations. Data were derived from a single institution, which may limit the generalizability of our findings. The number of patients who underwent mPAB is small, as this technique is indicated for a very specific type of congenital cardiac disease physiology.mPAB is a useful and reproducible technique in patients undergoing ASO who require concurrent restriction of antegrade pulmonary blood flow through the reconstructed neopulmonary root. This technique may reduce the degree of neopulmonary root distortion associated with standard PAB in this context and clearly eliminates the possibility of complications associated with distal band migration . Key to The authors reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The


Interestingly, the right ventricle of apoE−/− rats fed a high-fat diet showed more damage and affected collagen content  compared with the left ventricle . In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy , but also with right ventricle dysfunction with decreased TAPSE  and increased in systolic pulmonary artery pressure . Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE’s role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages  besides the known predisposition for obesity and affected lipid metabolism . Heart tissue also showed significant morphological changes in apoE Apolipoprotein (apo) E abnormality and disturbed lipid transportation represent well-known risk factors for cardiovascular diseases ,2,3. HowapoE genotypes: three homozygotes  and three heterozygotes . The ε3ε3 genotype is considered wild-type [apoE gene and imitating the genetical deletion in animal models. Besides the risk for developing atherosclerosis, ε4 allele carriers also seem to develop dilated cardiomyopathy [There are six different ild-type , as it imyopathy . Dilatedmyopathy .Since the involvement of apoE in the pathology of dilated cardiomyopathy is still not known, the aim of the study is to investigate the lipid-independent effects of apoE on heart tissue and the possible correlation with non-ischemic heart pathology in animals and humans.−/−) rats were analyzed.Time- and diet-dependent changes in blood composition in apoE knockout  with advanced heart failure (mean age 66 ± 8.68 years) were included: 50 with ischemic cardiomyopathy (ICM) and 61 with dilated cardiomyopathy (DCM) A. The diapoE genotype between CM patients and the control groups . CM patients presented a significant increase in the ε3/ε4 genotype frequency compared to the controls . Further, the frequency of allele ε2 was higher in the CM patients , whereas as expected, the frequency of the ε3/ε3 genotype was found to be significantly higher in the controls compared to patients .There was a significant difference in l groups A. We foup = 0.019)  B. HoweveSince the ε4 allele seems to correlate with increased cardiovascular events [There were no significant differences between the functional parameters between different genotypes; however, the ε2/ε4 genotype showed a non-significant trend towards reduced LVEF A, higher+/+  and apoE−/−  [All animal experiments were performed after approval (AZ 84-02.04.2012.A277), according to the European legislation and according to the FELASA guideline for the care and use of experimental animals. Eight-week-old apoEBlood analysis, including the concentration of lipids , protein and glucose, uric acid, creatinine, as well as differential blood cell count, was performed at different time points after starting the diet.At the end-point (after 20 weeks), rats were euthanized using cervical dislocation and were subjected to necropsy examination and the organs were immediately fixed in 4% neutral buffered formalin. The collected organs  were excised, processed, embedded in paraffin, and cut into 5 µm thick sections. Sections were stained with Hematoxylin and Eosin (HE) and elastin van Gieson stain for the identification of elastic, muscles and collagen fibers and analyzed for different histological features using a light microscope.For the semiquantitative pattern characterization of organ structure alterations, we modified current scoring methods ,10,11 toFor morphometric quantification, defined images of all hearts were obtained. Right and left ventricular wall thickness and ventricular cavity dimensions were quantified. Sirius red staining of the heart tissue was performed to quantify total collagen content in normal light and collagen type I and III in polarized light using Image J .Technical limitation: due to the fact that adequate equipment for measuring heart function in rats was missing, we limited our animal analysis to morphological parameters.A total of 120 Caucasian patients with heart failure (CM group) and 190 healthy outpatients (control group) were randomly selected between August 2017 and September 2019 from the Department of Cardiovascular Medicine of the University of Medicine and Pharmacy  and included in the study. The local ethics committee approved the study protocol (No. 20/26.02.2016) and written informed consent was obtained before study enrollment from all patients.2  and/or left ventricular end-diastolic volume >75 mL/m2, measured by transthoracic echocardiography; (2) a history of myocardial infarction or evidence of clinically significant  coronary artery disease (the ischemic CM = ICM); and (3) dilation and impaired contraction of left ventricle or both ventricles of idiopathic, familial/genetic, viral and/or immune, toxic origin, or associated with recognized cardiovascular disease in which the degree of myocardial dysfunction is not explained by normal loading conditions or the extent of ischemic damage (non-ischemic CM = DCM).The inclusion criteria included: (1) left ventricular ejection fraction <45% and/or left ventricular shortening fraction <25%; left ventricular end-diastolic diameter >3.2 cm/mThe exclusion criteria included: (1) acute myocardial infarction, unstable angina or percutaneous coronary intervention (PCI) within 90 days before screening, or CABG surgery within 180 days before screening; (2) previously underwent cardiac surgery with a remodeling procedure, left ventricular assist device placement or cardiomyoplasty; (3) cardiac resynchronization therapy (CRT) within 6 months (180 days) before screening; and (4) active myocarditis, constrictive pericarditis, restrictive, significant valvular heart disease, hypertrophic or congenital cardiomyopathy.The healthy volunteers were recruited based on the following criteria: (1) no symptoms of cardiovascular dysfunction, (2) normal ECG, and (3) no history of chronic disease. Clinical parameters  for each participant were collected.Collected data were (1) anthropometric data , body mass index (BMI)); (2) clinical data ; (3) rest 12 leads electrocardiogram ; (4) transthoracic echocardiography ; (5) laboratory analysis .Routine echocardiographic examinations were performed at the echocardiography core facility ,13. The Blood chemistry levels: total blood count, concentration of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, uric acid, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, glycemia and erythrocyte sedimentation rate, were performed at the hospital laboratory facility. In addition, blood samples from all participants were collected in tubes containing ethylenediaminetetraacetic acid (EDTA) and transported to the genetic human laboratory. After centrifugation, serum samples were stored at −80 °C until analysis while the sediment was stored at −20 °C until DNA extraction.® Genomic DNA Purification Kit . Approximately 100 μL of DNA was obtained at the end of the procedure. The purity and concentration of DNA were measured by a Nanodrop 2000  with DNA concentrations (mean = 112 ± 9.8 ng/μL) and optical density ratios (at 260/280 nm) (mean = 1.9 ± 0.2). Isolated DNA samples were preserved and stored at −20 °C until genotyping assessments were conducted.Genomic DNA was extracted from 300 μL of peripheral centrifuged blood. The isolation procedure was performed using a Wizard apoE genotype variants was performed using the protocol from Main BF et al. [The analysis of F et al.  that we ® DNA Polymerase for PCR. The total volume in each PCR reaction was 22 µL, including 5X GoTaq ® Green, MgCl2 (50 mmol/L), dNTP (10 mmol/L), primers (20 pmol), template DNA, GoTaq ® DNA Polymerase (4U) and ddH2O. Each PCR reaction contained the common primer (primer H) and one of the allele-specific primers. Therefore, four reaction mixtures were required per subject for genotype diagnosis. PCR reaction condition: after an initial DNA denaturation at 96 °C, 40 cycles of denaturation were performed at 96 °C, annealing at 58 °C and extending at 65 °C.PCR amplification was performed in an automated thermocycler  using the Promega kit GoTaq After PCR amplification, the samples were run on a horizontal electrophoresis system for 40 min, at 150w/150A over 2% agarose gel stained with Peqgreen to highlight the bands of the DNA. A CCD camera system  was used to visualize the banding patterns. The banding patterns were then compared to the known apoE primer combination of every genotype .t-test, more than two groups with 1-way ANOVA followed by Tukey’s post hoc-test, and more than 2 variables with 2-way ANOVA and Tukey’s multiple comparison test, as indicated. p-values of <0.05 were considered significant.Data represent the mean ± SEM. Statistical analysis was performed with Prism 6.1 software (GraphPad). Means of two groups were compared with unpaired Student’s t-test or with one-way ANOVA, followed by Tukey’s Multiple Comparisons testing, and statistical differences between categorical variables were determined with Chi Square test.Baseline characteristics were assessed by standard descriptive statistics. Continuous variables are presented as the mean ± standard deviation (SD). Categorical variables are presented as a frequency and percentage. Statistical differences between continuous variables were determined with Student’s p-value of <0.05 was regarded as statistically significant.Individuals homozygous for the common genotypic variants were used as the reference to test for any association by calculating the odds ratio (OR) with a 95% confidence interval (CI). Statistical analysis was performed with SPSS 22.0 . A −/− rats, the lung showed more edema and thickness of the alveolar wall, while the spleen showed more lymphoid hyperplasia in apoE−/− compared with wild-type rats.In this study, we showed that apoE-deficient rats present multiple organ damages besides the known predisposition for obesity and affected lipid metabolism. They showed increased retention parameters, mostly after the high-fat diet, and kidney injuries, such as vacuolization, congestion and glomerular thickening. The liver showed also signs of hepatocellular vacuolization, fat deposition and focal necrosis in apoE−/− rats, mostly after the high-fat diet, such as loose interstitial tissue, focal necrosis and edema. Interestingly, the right ventricle and not the left ventricle of apoE−/− rats fed the high-fat diet showed increased bundles of thin tissue and mononuclear cell infiltration. The dimensions of both ventricles were not different; however, the collagen content seemed to only be significantly affected by apoE deficiency in the right ventricle. Similarly, the collagen1/collagen3 ratio was only increased in the right ventricle of apoE−/− rats, suggesting significant changes in the extracellular matrix in the right ventricle compared with the left ventricle.Heart tissue showed significant morphological changes in apoEIn patients, we were able to find a correlation between the presence of the ε4 allele and cardiomyopathy, but not with the etiology of the cardiomyopathy (ischemic or dilatative). While Jurkovicova et al. found ε2/ε4 as the predominant genotype in patients with dilated cardiomyopathy , we founThe missing or dysfunctional apoE protein, such as apoE4, is always associated with increased intracellular cholesterol and lipid accumulation and accompanied by cardiomyopathy and cardiac diastolic dysfunction ,17,18. RFurthermore, apoE was found to be significantly increased in apoptotic bodies , which iThe architecture of the heart is made to support a huge biomechanical burden. The fibroblasts are responsible for sustaining the cardiomyocytes’ function but also for the qualitative and quantitative maintenance of the extracellular matrix. Under physiological conditions, fibroblasts are arranged in layers and strands, and are elongated and flattened cells that border on cardiomyocytes in an endomysial collagen network. This distribution model suggested from the very beginning the fundamental role of all the structures of the heart in taking over the tensile forces that appear at the parietal level . MoreoveRecently, more studies are emphasizing a major effect of lipoproteins on cardiac function independent of coronary artery disease. For example, cholesterol-lowering therapy can reduce oxidative stress and decrease levels of tumor necrosis factor alpha, thus counteracting structural and metabolic remodeling, enhancing cardiac function , attenuaInterestingly, it seems that there is a difference between the left and right ventricle fibroblasts. In the absence of injury, right and left ventricular fibroblasts appear to have similar characteristics. However, the right ventricle has unique characteristics that make it susceptible to certain genetic conditions associated with interstitial remodeling, such as arrhythmogenic right ventricle cardiomyopathy. Other studies showed that the perturbation of the collagen1/collagen3 ratio may be responsible for the increase in right ventricular stiffness ,36,37. T−/− rats presented more thin tissue bundles and mononuclear cell infiltration and an increased collagen1/collagen3 ratio, while these factors remained unchanged in the left ventricle. Similarly, the ε4 allele carriers showed significantly higher right ventricular dysfunction. Recently, some studies showed that apoE deficiency appears to be a novel risk factor for pulmonary artery hypertension (PAH) and patients with PAH have reduced expression of apoE in their lungs [−/− mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. Atherosclerosis and PAH have the same pathophysiological processes, such as endothelial dysfunction and increased inflammatory mediators such as IL-6 [In the present study, we observed that the right ventricle of apoEir lungs ,39. Addi as IL-6 . This coBesides technical limitations regarding the missing equipment for performing echocardiography in rats, we can consider the absence of more advanced imaging such as Speckle-tracking echocardiography or cardiac MRI that would enable the better analysis of the right and left ventricular dysfunction as a limitation. However, the acquired conventional echocardiography data were enough to provide solid data and significant correlations for the current study. The small population size most likely did not affect the results because the presence of the ε4 allele was significantly higher in the CM population, similar to other cohorts. Further, our study was more of an observational study based on a case–control design. However, since this is the first article reporting the relation between the presence of the ε4 allele and right ventricular dysfunction, the results should be further validated in a specific risk population.Our results confirm that the presence of the ε4 allele is an independent risk factor for heart failure, independent of etiology and lipid metabolism. The underlying mechanisms remain to be elucidated. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and extracellular matrix in both ventricles. It is essential that this is considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.