Several studies have demonstrated that severe tricuspid regurgitation (TR) has a significant negative impact on morbidity and mortality. Nowadays, several therapeutic options to treat TR are available and patients at high surgical risk can also be treated with transcatheter procedures. For the management of patients with TR, an accurate assessment of the tricuspid valve and its surrounding structures is therefore of crucial importance and has gained significant interest in the medical community. Different imaging modalities can provide detailed information on the tricuspid valve apparatus, right ventricle, right atrium, and coronary circulation which are fundamental to define the timing and anatomic suitability of surgical and percutaneous procedures. The present review illustrates the role of 2D and 3D echocardiography, cardiac magnetic resonance, and multidetector row computed tomography for the assessment of the tricuspid valve and right heart with a particular focus on the data needed for planning and guiding interventional procedures. The tricuspid valve (TV) apparatus is a complex structure consisting of three leaflets inserted in the tricuspid annulus (TA) and connected to the papillary muscles of the right ventricle (RV) through the chordae tendinae . The funCurrent American and European guidelines recommend TV interventions (preferably TV repair) at the time of left-sided valve surgery in case of severe TR (class I) or in the presence of TA dilation regardless of TR severity (class IIa) , 10. On The TV is the atrioventricular valve located between the RA and RV  with a mThe identification of the potential mechanisms underlying TR represents the first step in the evaluation of patients with TR. The causes of TR can be grouped into two main categories, primary TR and secondary TR  Figure . PrimaryTransthoracic two-dimensional (2D) echocardiography is the pivotal imaging modality to evaluate the TV apparatus, RA and RV due to its wide availability. Echocardiography provides fundamental information regarding the anatomy and specific lesions of the leaflets and whole valvular apparatus, including surrounding structures which are very important to identify the etiology of TR . Conside2 is indicative of TA dilatation. In secondary TR, the TA dilates more posteriorly and its shape becomes more circular as TR becomes more severe. Accordingly, it had been demonstrated that 2D echocardiography systematically underestimates the TA diameter compared to a 3D assessment  is characterized by high spatial resolution which makes this imaging modality ideal to assess the TA dimensions and the relationship of the TA with the RCA which are fundamental to plan interventional procedures on the TA  . The quaCardiac magnetic resonance (CMR) is the gold standard imaging modality to evaluate RV size and systolic function without the use of contrast media . HoweverEchocardiography represents the mainstay imaging modality to grade TR severity . AccordiThe qualitative parameters of TR severity are not based on mathematical formulas but mainly on the subjective assessment of the physician and therefore are largely dependent on experience and come with limitations. A large color Doppler flow convergence in the ventricular side of the TV throughout the systole suggests severe TR. However, this parameter is highly dependent on the settings of the machine, loading conditions and can underestimate TR severity in the presence of eccentric jets. Moreover, the density, timing and shape of the continuous wave Doppler jet of TR can be informative on TR severity. A dense, holosystolic, with an early peak TR jet is suggestive of severe TR.2 indicates severe TR and the same applies to a ratio between the regurgitant jet area and RA area > 33%. The vena contracta (VC) width is another semi-quantitative parameter of TR severity and represents the diameter of the narrowest portion of the regurgitant jet immediately downstream of the regurgitant orifice. A VC width ≥ 7 mm is consistent with severe TR. A proximal isovelocity surface area (PISA) radius ≥ 9 mm  is also indicative of severe TR. The presence of systolic reversal flow in the hepatic vein (sampled with pulse wave Doppler) represents a specific but not sensitive parameter of severe TR because it is largely affected by the direction of the jet and by the presence of atrial fibrillation. Finally, the evaluation of the tricuspid inflow pattern with the pulsed-wave Doppler can indicate the severity of TR. A prominent E wave (>1.0 m/s) is usually present in patients with severe TR; nevertheless, the tricuspid inflow pattern is highly affected by the cardiac rhythm and should not be taken into account as an index of TR severity in patients with atrial fibrillation.Semi-quantitative parameters of TR severity provide a more detailed picture on TR severity compared to a qualitative assessment. A color Doppler TR jet area > 10 cm2 and a regurgitant volume ≥ 45 ml/beat are suggested by the guidelines to identify severe TR  and regurgitant volume based on the PISA method. Although, EROA can be underestimated in the presence of an elliptic orifice, recent studies have shown an important relation of this parameter with prognosis in patients with significant TR . An EROAevere TR .2) and torrential TR (VC width ≥ 7 mm and EROA ≥ 80 mm2) showed to be useful to predict patient outcomes in patients with significant secondary TR , the systolic excursion velocity of the lateral portion of the TA (S') and RV fractional area change (FAC) are the most widely used standard 2D echocardiographic parameters of RV systolic function . TAPSE iAll the conventional echocardiographic parameters are highly affected by loading conditions and may not be representative of RV contractility. Speckle-tracking echocardiography (STE) is angle independent and the STE-derived global and free-wall longitudinal strain are less load dependent parameters of RV systolic function . RV globThe complex RV geometry and systolic function can be better assessed with 3D imaging techniques. Although still challenging by suboptimal quality of the acoustic window, 3D echocardiography can be useful for an accurate assessment of RV volumes and to calculate RV ejection fraction . An exceDifferent surgical and percutaneous options are currently available for the treatment of TR and, similarly to other valvular heart disease , multimoIn patients undergoing cardiac surgery for other indications or not at high surgical risk, surgery represents a valuable option to treat TR. Overall, surgical TV repair should be preferred over TV replacement because, when feasible, it is associated with less complications and better outcomes . The aimIn patients at high or prohibitive surgical risk or without the need of other cardiac surgeries, a transcatheter procedure to treat TR can be considered. Different options exist and again the choice should be based on the pre-procedural assessment and identification of the mechanism of TR, mainly using echocardiography. In patients where the dilation of the TA is the main mechanism causing TR, a transcatheter direct annuloplasty represents a valuable option and three systems are currently available: the Trialign system, the TriCinch device, and the Cardioband system. The Trialign is a suture based TV direct annuloplasty system that reduces the TA diameter through tissue plication . From a The Cardioband system is the percutaneous equivalent of the surgical undersized annuloplasty. This system consists of an adjustable, sutureless annuloplasty band of polyester through which anchors are inserted . The sysAnother percutaneous option to repair the TV is represented by the devices that can restore the TV leaflet coaptation. The Triclip system is an adaptation of the Mitraclip system to the TV. Both the Mitraclip and the Triclip systems can be used to achieve a percutaneous edge-to-edge repair of the TV and are useful to treat either primary or secondary TR . Two sizTranscatheter TV replacement represents a valuable option in the case of failing TV annuloplasty or biological TV prosthesis. Prostheses normally applied in the aortic position have been successfully used for valve-in-ring or valve-in-valve procedures on failing TV annuloplasty or biological TV prosthesis . A meticFinally, transcatheter valves can be implanted in the superior and/or inferior caval veins to reduce the backflow of blood from the incompetent TV to the caval veins and reduce symptoms and signs of venous congestion. The implantation of balloon-expandable valves requires pre-stenting of the inferior vena cava to downsize the landing zone and ensure safe anchoring of the transcatheter valve . On the Similar to transcatheter procedures on heart valves other than the TV, intraprocedural guidance of percutaneous procedures on the TV relies on multimodality imaging . 3D tranTransthoracic 2D/3D echocardiography is the main imaging modality used for the follow-up of patients after surgical or percutaneous procedures on the TV. Several information should be assessed and recorded. First, it is very important to assess residual TR before discharging the patient as it may differ from the evaluation performed in the immediate post-procedural phase in the operating theater where the patient might have been under general anesthesia, invasive ventilation or sedation with different RV loading conditions. Qualitative, semi-quantitative and, most importantly, quantitative parameters of TR severity should be recorded  to allowThe accumulating evidence on the negative prognostic impact of TR and the development of effective transcatheter procedures to treat also patients with multiple comorbidities and at high or prohibitive surgical risk have increased the interest on the imaging of the right heart and TV. Multimodality imaging plays a key role to assess TR severity, TA dimensions, RV and RA remodeling, define the etiology of TR, choose the timing and the best therapeutic option, guide the procedure, prevent complications and follow-up patients with significant TR after interventions.FF wrote the first draft of the manuscript and prepared the figures and adjusted it according to the comments and suggestions of the co-authors. KH helped in preparing the figures and critically revised the manuscript. JB and VD critically revised the manuscript. NA helped in structuring the manuscript, preparing the figures, and critically revised the manuscript. All authors contributed to the article and approved the submitted version.The Department of Cardiology of the Leiden University Medical Center received research grants from Abbott Vascular, Bayer, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare, Ionis, and Edwards Lifesciences. JB received speaking fees from Abbott Vascular. VD received speaker fees from Abbott Vascular, Medtronic, Edwards Lifesciences, Novartis, MSD, and GE Healthcare. NA received speaker fees from Abbott Vascular and GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart failure (HF) is a serious, chronic disease, causing significant ill health and high mortality worldwide. The current clinical strategies emphasize reducing the transition from a healthy to a failing heart despite the shift in the clinical goal from healing to disease prevention. Recent research advancements on noncoding RNAs (ncRNAs) have demonstrated that circular RNAs (circRNAs) are significant therapeutic targets in HF. Previous studies have highlighted the potential applicability of circRNAs in the diagnosis and treatment of diseases. However, less is known regarding the potential benefits of circRNAs as novel diagnostic and treatment biomarkers for HF. In the present study, we summarize the current developments and achievements associated with the use of circRNAs as HF biomarkers. We also discuss future research directions regarding HF diagnosis and treatment. Heart failure (HF) is attributed to several cardiovascular diseases (CVDs), including, cardiac hypertrophy, myocardial fibrosis, and ischemic cardiomyopathy. In 2000, the prevalence of chronic heart failure (CHF) in the Chinese population aged 35–74 years was 0.9%, and CHF prevalence was found to significantly increase with age. The China Heart Failure Patient Registration Research (China-HF) analyzed data from 8516 patients with HF admitted in 88 participating hospitals from 2012 to 2014 and reported a significant increase in the average age of patients hospitalized with HF. Hypertension and coronary heart disease are reported as the main causes of HF in China, and infections have been implicated in the pathogenesis of HF. Currently, the mortality rate after hospitalization with HF is 4.1% in China from 2014 to 2018, which is significantly lower than the rate in previous years. Patients with HF present with nonspecific symptoms and are difficult to distinguish from those of other cardiovascular diseases. Some of the symptoms presented by patients with HF include dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. In addition, the lack of adequate cardiac output can cause fatigue, weakness, and exercise intolerance. The clinical diagnosis of HF based on clinical manifestations is challenging and may lead to a definitive diagnosis and delayed treatment, thereby causing inaccurate prognosis .Consequently, accurate and effective diagnostic measures are needed in clinical practice to distinguish HF from other cardiovascular diseases. Currently, medical history, physical examination, and chest X-rays are the traditional clinical assessment approaches for patients suspected to have HF. However, isolated signs and symptoms cannot be objectively assessed for HF diagnosis . With reB-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have been widely used as diagnostic biomarkers for HF . In addiOver the last few years, the noncoding RNAs have attracted significant interest in the scientific community. High-throughput RNA-sequencing analysis of the genome has shown that 70% of the human genome is transcribed, but only 2% code for proteins . RegulatOver the past few years, research on noncoding RNAs implicated in the pathogenesis of HF has rapidly progressed and is still ongoing. Similar to miRNAs and lncRNAs, circRNAs are a class of noncoding RNAs, but unlike linear RNAs, circRNAs form a closed continuous loop, signifying that the structure has neither 5’ caps nor 3’ tails . circRNAvia an AAV9-based vector system would result in HF via regulating the expression of serum response factor (Srf), connective tissue growth factor (CTGF), β1-adrenergic receptor (β1-AR) via miR-133a or adenylate cyclase 6 (Adcy6) directly. Interestingly, the expression of Adcy6 is also affected by circ-HPIK3 (via regulating Ca2+ load and transient (via transcription factor cAMP responsive element-binding protein 1 (CREB1). Circ-HPIK3 would impair the function of heart via increasing Ca2+ concentration by the circ-HPIK3-miR-17-3p-Adcy6 axis in the long run and might be a therapeutic target of HF.CircRNAs involved in HF are widely discussed.  and in vivo transgenically would induce a hypertrophy phenotype. CircRNA_000203 could sponge miR-26b-5p and miR-140-3p and abolish the synergistic inhibition of Gata4, a pro-hypertrophy factor. Furthermore, NF-κB signaling also took part in cardiac hypertrophy regulated by circRNA_000203.CircRNAs involved in HF have been widely discussed because cardiac hypertrophy contributes to HF. Heart-related circRNAs (circRNAs HRCR) are reported to attenuate cardiac hypertrophy by targeting miR-223. The expression of circRNA HRCR is reduced in thoracic aortic constriction (TAC) and isoproterenol-induced cardiac hypertrophy mouse models . The expertrophy . Overexpin vitro through sponging miR-4793-5p. These circRNAs attenuate the development of HF by regulating the proliferation of cardiomyocytes after MI.In addition, ischemic-induced cardiac remodeling is also an important promoter of HF. Myocardial infarction (MI) is an ischemic cardiomyopathy caused by insufficient coronary blood supply and induces necrosis and apoptosis of cardiomyocytes. The remaining cardiomyocytes cannot achieve self-repair and are forced to undergo compensatory hypertrophy. At the same time, the proliferation of fibroblasts is activated, resulting in ventricular remodeling and myocardial fibrosis. A long-term cardiac workload will eventually lead to HF . It is rvia interaction with RNA binding protein FUS  is an important mechanism to induce ventricular remodeling. Silencing circRNA 010567 in the rat model of acute MI established that using ligation of the left anterior descending coronary artery would improve cardiac function, higher ejection fraction, and fractional shortening and alleviate MF through the TGF-β1 signaling pathway . A cardiThese findings demonstrate that circRNAs have potential regulatory functions in HF and inhibit symptoms that can induce HF, including hypertrophy, cardiomyocyte apoptosis, and ventricular remodeling. Interestingly, circRNAs have been detected in the bloodstream , signifySimilar to miRNAs and lncRNAs, circRNAs also have the potential of being used as biomarkers of HF and can even be more effective than miRNAs and lncRNAs. First, circRNAs have excellent stability associated with their circularized structure, which protects them from endonuclease activities . TherefoThere is increasing evidence indicating that the expression of specific circRNAs is dysregulated in cardiovascular disease. For example, hsa_circ_01224644 has been reported as a potential biomarker of coronary artery disease due to its upregulation during the progression of the disease . In addin=86), ST-elevation MI (n=270), and non-ST-elevation MI (n=139). The expression of MICRA in healthy volunteers and MI patients are significantly different, but there were none in ST-elevation or non-ST-elevation MI. In this trial, the expression levels of MICRA were measured by quantitative PCR. Beyond this, left ventricular function, ejection fraction and demographic and clinical variables were assessed at a 4-month follow-up to evaluate the subjects’ heart condition. Furthermore, the patient also maintained the use of the listed circRNAs in the diagnosis of HF, indicating that circRNA MICRAs can be used as biomarkers for HF (p<0.0001). Notably, correlation analysis shows that the expression of hsa_circ_0062960 is highly positively correlated with the serum level of BNP, signifying its potential role as a biomarker of HF (A previous study demonstrated that the expression of circRNA referred to as MI-associated circular RNA (MICRA) is reduced in patients with acute MI compared with healthy people and may act as a predictor of the risk of left ventricular dysfunction after acute MI. MICRA is also downregulated in patients with decreased ejection fraction, suggesting its potential role as a HF biomarker . Recentls for HF . In addier of HF .There were three circRNAs identified as potential biomarkers for the hypertrophic cardiomyopathy (HCM) . Serum eP < 0.05) and associated with CVD (P < 0.0001). Has_circ_0005540 also showed a high discriminatory power for CVD in ROC analyses . These results suggest that plasma exosomal has_circ_0005540 could be used as a promising biomarker of CVD. Exosomes extracted from peripheral blood samples of patients with HF and healthy patients (control group) were analyzed using next-generation sequencing, and the results indicate that the expression of has_circ_0097435 was upregulated in patients with HF. The high expression of hsa_circ_0097435 in exosomes demonstrates that most hsa_circ_0097435 are encapsulated in the exosomes, confirming that hsa_circ_0097435 is a potential biomarker of HF .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Even with a small number of cases, CNN-based contouring for rTOF can be improved. This work should be extended to other forms of congenital heart disease with more extreme structural abnormalities. Aspects of this work have already been implemented in clinical practice, representing rapid clinical translation. The combined use of both spatial and volumetric comparisons yielded insights into algorithm errors.Ventricular contouring of cardiac magnetic resonance imaging is the gold standard for volumetric analysis for repaired tetralogy of Fallot (rTOF), but can be time-consuming and subject to variability. A convolutional neural network (CNN) ventricular contouring algorithm was developed to generate contours for mostly structural normal hearts. We aimed to improve this algorithm for use in rTOF and propose a more comprehensive method of evaluating algorithm performance. We evaluated the performance of a ventricular contouring CNN, that was trained on mostly structurally normal hearts, on rTOF patients. We then created an updated CNN by adding rTOF training cases and evaluated the new algorithm’s performance generating contours for both the left and right ventricles (LV and RV) on new testing data. Algorithm performance was evaluated with spatial metrics (Dice Similarity Coefficient (DSC), Hausdorff distance, and average Hausdorff distance) and volumetric comparisons . The original Mostly Structurally Normal (MSN) algorithm was better at contouring the LV than the RV in patients with rTOF. After retraining the algorithm, the new MSN + rTOF algorithm showed improvements for LV epicardial and RV endocardial contours on testing data to which it was naïve  contains supplementary material, which is available to authorized users. Early uses of neural networks in medicine used hundreds of thousands of cases to show physician-level accuracy in image-based diagnoses, e.g., for skin cancer  and diabCardiovascular magnetic resonance (CMR) imaging is a non-invasive and safe imaging modality, and its use is growing in congenital heart disease. CMR is generally considered to be the gold standard imaging modality for ventricular volume and function measurement, as calculating these parameters can be done with minimal spatial assumptions as compared to echocardiography –12. TetrVentricular volumes and function are calculated through contouring, where the endocardial and epicardial surfaces of the ventricular muscle are outlined, then summed using the method of disks . Contourhttp://biobank.ndph.ox.ac.uk/showcase/field.cgi?id=21003), with generally structurally normal hearts. The protocol for the UKBB has been described [Recently, machine learning techniques, namely neural networks, have been developed to automate ventricular contouring. For instance, Bai et al.  recentlyescribed .As noted, most machine learning CMR contouring tools are trained on adults with structurally normal hearts. Other approaches to addressing the issue of training algorithms with small numbers of cases of congenital heart disease also have been proposed , though Given the importance of CMR values, especially RV values, on decision making for children and adults with rTOF, it is vital to improve contouring in congenital heart disease to reduce contouring time and potentially reduce variability. Thus, we evaluated a CNN that was trained on UKBB data combined with selected other pathologies such as hypertrophic cardiomyopathy, but no congenital heart disease. We evaluated its performance on left ventricular (LV) and RV contouring in rTOF, testing LV epicardium (LV epi), LV endocardium (LV endo), and RV endo, at end diastole (ED) and end systole (ES), as these are the contours most commonly drawn clinically. We hypothesized that the algorithm would be worse at contouring the RV than the LV given the more complex shape of the RV and higher likelihood of RV dilation in rTOF, and that adding rTOF training data for the algorithm would improve both LV and RV contouring in rTOF. Our study is novel because we examined a potential method to solve the problem of small case numbers in pediatric cardiology. By using an existing algorithm, trained on a large number of adult datasets, testing it on congenital CMRs, and then improving it with a small number of congenital CMRs, we can evaluate whether this strategy could be viable for other uses of machine learning in pediatric cardiology as well. Further, we evaluated the performance of the algorithms using both spatial- and volumetrics.Patients were included that had a diagnosis of tetralogy of Fallot with pulmonary stenosis or atresia that had undergone initial repair and underwent a follow-up CMR study at our institution between 1/2016 and 7/2019. Patients with tetralogy of Fallot with absent pulmonary valve were excluded. This study was performed under UTSW IRB STU 122017–037.The rTOF cases were divided into two groups by time, with the earlier cases assigned to the training dataset. This training dataset was used to evaluate the initial CNN for use in rTOF, and then used to retrain the CNN. The more recent cases were assigned to the testing dataset and were used to compare performance of the initial  and revised (MSN + rTOF) contouring algorithms.CMR was performed on a 1.5T Ingenia scanner  using a 32-channel torso phased-array digital receiver coil. ECG gated balanced cine steady-state free precession images (bSSFP) were obtained in a short-axis stack of 9–13 slices from above the atrioventricular valves to the apex, in 30 phases per cardiac cycle with a slice thickness of 8–10 mm, no gap, field of view between 272 mm × 272 mm and 390 mm × 390 mm, echo time 1.11–1.68 ms, temporal resolution at a median of 34.5 ms (25.3–50 ms). The cines were performed with breath-holding technique if possible, otherwise, 2 signal averages were used in combination with respiratory bellows gating for patients who could not perform a breath hold. There were no changes to the bSSFP sequence through the study, and hence the same sequence was used for patients in both the training and testing datasets.Manual contouring of the rTOF training and testing datasets was done for clinical purposes using standard post-processing practices as described by Fratz et al.  using cvThe machine learning algorithm employed herein to predict ventricular contours was a CNN based on the U-net architecture . The CNNThe initial CNN was trained on the UKBB CMR dataset on ~ 5000 CMR studies, as well as a set of 100 pathologic CMR studies including cases of hypertrophic cardiomyopathy, dilated cardiomyopathy, and myocardial infarction, but no rTOF cases. Given that these are mostly normal hearts, we labeled this algorithm the Mostly Structurally Normal (MSN) algorithm. The MSN algorithm is available in Circle cvi42 version 5.9 .The CNN was trained on images with spatial resolution of 198 × 198 pixels with a pixel spacing of 1.855 × 1.855 mm/pixel. This allowed the network to be trained on images with varying field-of-views and acquisition specific resolution. Batch normalization layers are used to standardize the intensity of input images. To increase the generalizability of the network, image augmentation techniques such as rotation, scaling, translation, and mirroring were applied to the input data. Early stopping was also used to avoid overfitting. No other regularization techniques, i.e., dropout or weight decay, were used during the training of this network.The cvi42 software uses a proprietary, heuristic-based algorithm to post-process the results of the CNN into contours that reside in a 4 × 4 subpixel space of the original input image. All results reported in this paper are reported on the post-processed cvi42 contours.The manual rTOF contours from the training dataset were then used to retrain the MSN algorithm to yield the MSN + rTOF algorithm. This was accomplished by incorporating the rTOF training data into the pool of MSN training data. During training stage of the MSN + rTOF algorithm, the number of rTOF cases was oversampled in each training epoch to ensure that the CNN does not learn to ignore the rTOF cases in the early stages of training since the > 5000 MSN data vastly outnumber the rTOF instances. The rTOF images were processed to match the spatial resolution for which the MSN network was trained. Aside from changes to the training data, the exact same CNN architecture and optimization parameters were used in the MSN and MSN + rTOF experiments. The same cvi42 post-processing algorithm was used for this network.The manually generated contours used for clinical reporting were considered the gold standard contours and thus were the basis for all comparisons.Contours were analyzed using both spatial- and volumetrics. In terms of spatial metrics, the Dice Similarity Coefficient (DSC) represents spatial overlap in three dimensions and is calculated using the formula DSC = (2*(A ∩ B)/(A + B)) where A ∩ B represents the volume of the spatial overlap, and A and B represent the volumes of the original clinical ventricular contour and comparison contour, respectively . A DSC oThe ventricular end-diastolic volumes (EDV), end systolic volumes (ESV), and ejection fractions (EF) were compared between contouring methods by assessing the absolute value of the percentage difference in volume or EF as compared to the manually calculated volumes (%error).p < 0.05 was considered significant. Statistical analyses were performed using GraphPad Prism version 8.1 .For patient characteristics, Mann–Whitney and t-tests with Welch’s correction were used. For spatial comparisons, Wilcoxon signed-rank tests were used. For volumetric comparisons, Wilcoxon matched-pair signed-rank test, linear correlation, and Bland–Altman analyses were performed. In all cases, To determine intra- and interrater variation of contours, half of the patients in the testing dataset had contours redrawn by the original contourer (VG), as well as another expert in CMR with 6 years’ experience (BEUB). Intra- and interrater spatial- and volumetrics were calculated.Patients were sorted by worst performance on spatial and volumetric measures on both MSN and MSN + rTOF, and those whose performance declined the most from MSN to MSN + rTOF. The six cases that appeared most commonly in these lists were manually reviewed to find patterns that could explain poor algorithm performance.In addition, we analyzed the data again after removing algorithm-generated contours in slices where there were no manual contours.The rTOF training dataset initially consisted of 59 cases, but the CNN was designed to train on cases where both LV and RV contours were in the same cardiac phase, so 57 cases could be used for diastole, and 31 for systole. The rTOF testing dataset was initially 32 cases, but for similar reasons only 30 were used. The technical exclusion rate is similar to other such studies . PatientWe initially tested how well the MSN algorithm contoured the LV endo, LV epi, and RV endo for patients with repaired rTOF Fig. . The spaNext, we evaluated the performance of the MSN + rTOF algorithm on new rTOF cases (testing dataset) and compared it to the standard MSN algorithm. Thirty cases were used and analyzed using both spatial- and volumetrics.Regarding spatial metrics, LV epi and RV endo contours improved from MSN to MSN + rTOF in all three evaluation metrics , with LV endo also having an improved DSC .In this paper we evaluated a machine learning algorithm, a convolutional neural network (CNN), for ventricular contouring that was trained on mostly structurally normal hearts. We showed that this MSN algorithm did better for the LV than the RV in patients with rTOF across a number of different metrics, using both spatial and volumetric assessments by design. We then used those cases to create an improved algorithm MSN + rTOF. This improved algorithm showed clear benefits with spatial metrics, and improvements with some volumetric measures as well. This suggests that the MSN + rTOF algorithm learned improvements that generalize to studies beyond the training dataset.Most automated analysis tools are developed for structurally normal hearts, and fewer are designed specifically for congenital heart disease, likely because training these algorithms initially requires a significant volume of cases. Our work shows that even with small numbers of cases, an already established algorithm can be expanded to use in other clinical scenarios. Also, the inclusion of rTOF cases to generate the MSN + rTOF algorithm did not degrade performance on structurally normal hearts (industry-level testing data not shown), thus expanding the clinical utility of the algorithm.As the field of pediatric cardiology will always face the issue of lower numbers and clinical heterogeneity, these findings are of clinical importance. This work should encourage further investigation of modifying solutions to adult problems to fit the needs of patients with congenital heart disease and to find avenues to address more niche clinical needs that have smaller patient or image volumes.The performance of the MSN + rTOF algorithm was in general worse than intra- and interrater contours for the LV and in general not significantly worse than intra- and interrater contours for the RV. This is likely due to the higher intrarater differences in RV contouring. These findings are similar to Blalock et al.  who repoThere have been multiple studies examining automated contouring in adult CMR studies  and volumetric  measures to evaluate the performance of the algorithms on our datasets. DSC focuses solely on spatial overlap and thus is susceptible to overestimating performance if the central volume of the contours is correct despite the edges being less accurate. Because the shape of the ventricles is important for ventricular contouring as well as the volume, spatial distance-based metrics, namely, HD and AVD, were also used . VentricThe most common error made by the algorithms, and likely the source of the largest volumetric discrepancies compared to gold standard contours, was when they generated ventricular contours in slices that were beyond the base or apex of the ventricles. This is likely because the UKBB data, on which the algorithms were primarily trained, are generally limited to and rarely extend beyond the ventricles. Given the RV dilation often found in patients with rTOF, and the desire to evaluate atrial performance, our practice is to extend the short-axis slices past the LV apex and into the atria, to avoid missing parts of the dilated RV apex and RV “shoulder” that extend basally past the tricuspid annulus Fig. . PotentiThe data used were clinical data and thus were not subjected to extra data cleaning and revisions. We specifically chose clinical data because our goal was to use real-world datasets instead of curated ones.In the current form, this algorithm was limited to CMR studies where ES and ED were in the same cardiac phase for both the RV and LV. Given that this is not always the case , this represents a limitation of the current algorithm for use in clinical practice.We performed this study on rTOF cases as this is the most common indication for congenital CMR. However, in the spectrum of congenital heart disease, the cardiac structure in rTOF is likely more similar to structurally normal hearts than other types of pathology, e.g., single ventricle disease or L-transposition of the great arteries, other common indications for congenital CMR. Thus, it is possible that a similar retraining strategy may not be as successful in those cases of more complex disease.We showed that a CNN, developed for structurally normal hearts, was able to be adapted to use in rTOF with a relatively small number of training cases, with acceptable but not ideal spatial and volumetric performance compared to manually drawn contours. rTOF is the most common indication for congenital CMR, so these findings support the development of contouring tools to increase efficiency of the clinical and research workflows for rTOF CMR. This work should be extended to other forms of congenital heart disease where the structural abnormalities are more extreme compared to structurally normal hearts. Aspects of this work were also rapidly translated into clinical use.Electronic supplementary material 1 (DOCX 58 kb)Below is the link to the electronic supplementary material.


Aortic stenosis (AS) may lead to diastolic dysfunction and later on heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) via increased afterload and left-ventricular (LV) hypertrophy. Since epicardial adipose tissue (EAT) is a metabolically active fat depot that is adjacent to the myocardium and can influence cardiomyocytes and LV function via secretion of proinflammatory cytokines, we hypothesized that high amounts of EAT, as assessed by computed tomography (CT), may aggravate the development and severity of LV hypertrophy and diastolic dysfunction in the context of AS.We studied 50 patients  in this preliminary study with mild or moderate AS and mild to severe LV diastolic dysfunction (LVDD), diagnosed by echocardiography, who underwent non-contrast cardiac CT and echocardiography. EAT parameters were measured on 2nd generation dual source CT. Conventional two-dimensional echocardiography and Tissue Doppler Imaging (TDI) was performed to assess LV function and to derive myocardial straining parameter. All patients had a preserved LV ejection fraction > 50%. Data was analysed using Pearson’s correlation.Only weak correlation was found between EAT volume or density and E/é ratio as LVDD marker . Also, EAT volume or density were independent from Global Strain Parameters (r = 0.058 p = .688 and r = -0.207 p = .239). E/é ratio was strongly associated with LVDD (r = .761 p≤0.0001) and Strain Parameters were moderately associated with LV Ejection Fraction (r = -.669 p≤0.001 and r = -.454 P≤0.005).In this preliminary study in patients with AS, the EAT volume and density as assessed by CT correlated only weakly with LVDD, as expressed by the commonly used E/é ratio, and with LV strain function. Hence, measuring EAT volume and density may neither contribute to the prediction nor upon the severity of LVDD, respectively. Heart failure (HF) is distinguishable into systolic heart failure (SHF) with an impaired LV ejection fraction or diastolic heart failure (DHF) with impaired filling of the left ventricle . In DHF Aortic Stenosis (AS), as the most common valvular lesion in the western world , impairsMyocardial Deformation (Strain Imaging) analysis is an application of echocardiography to quantify LV function and enables for quantifying LV dysfunction. There are two options for Strain Imaging, tissue doppler derived strain imaging (TDI) or 2D speckle tracking echocardiography (STE). Both have been validated for myocardial deformation analysis . In thisEpicardial adipose tissue (EAT) is a metabolically active fat depot that makes up for approximately 20% of total heart weight and lies on top of the myocardium and in the interatrial grooves around the coronary arteries , 16. EATThe finding of a previous study that EAT is associated with the deterioration of diastolic function over time, fuells our hypothesis of possible disadvantageous local myocardial effects of EAT , 21, whihttp://www.clinicaltrials.gov. Unique identifier: NCT00785109; reviewed and approved by RWTH Aachen Institutional Review Board No. 165/08), where we retrospectively derived EAT parameters from CT datasets and included echocardiographic studies which measured LVDD and myocardial deformation (Strain)  within the pericardium were automatically quantified. Assessment for EATV was done below the pulmonary trunk till the end of the left ventricular apex to standardize the z-axis coverage. Total EATV was acquired by summing up the EAT area of all axial slices, multiplied by the slice thickness [3mm] and the number of slices.The echocardiographic studies were performed by two experienced cardiologists on a Vivid 7 Ultrasound System . Datasets were acquired for three full cardiac cycles with a frame rate of at least 50 frames/sec at three parasternal short axes  and three apical long axes [2- and 4-chamber views and at the apical level (APLAX)]. The mitral inflow E velocity was acquired by pulsed Doppler and é velocity was averaged from the septal and lateral mitral annuli. Strain Parameters were acquired in the endocardial, midmyocardial and the epicardial layer and averaged. Analysis of TDI images was performed offline with a customized software  by two independent observers. Evaluation of LV Diastolic Dysfunction was done in accordance with present guidelines and recommendations , 10.The statistical analysis was performed using IBM SPSS Statistics 23.0 . All continuous parameters are expressed as means ± standard deviations or n (%) where applicable. The distribution of the data was checked for normality using the Shapiro-Wilk test. Then the correlation between EAT parameters and indices of cardiac function assessed by TDI was evaluated with Pearson’s correlation. A 2-tailed p-value of <0.05 was set for statistical significance.2 (range: 19–36 kg/m2) and 16 (32%) were obese (BMI ≥ 30 kg/m2). For more details please refer to 50 Patients with a mean age of 71 ± 9 years were included in this study. Of those, 42 (84%) were male. 39 (78%) had arterial hypertension, 8 (16%) had diabetes mellitus, 25 (50%) had dyslipidaemia, 26 (52%) had coronary artery disease and 6 (12%) were active smokers. Mean observed body weight was 81 ± 13 kg, the average BMI in the study population was 27 ± 4 kg/m3]. Mean EAT density was -84.69 ± 14.46 [HU] and the mean noise index of EAT density was 25.48 ± 16.33 [HU]. EAT volume index [EATV], EAT volume normalised on body surface area [BSA], was 65.64 ± 21.95 [cm3/m2]. Male participants had a mean EAT volume of 129.60 ± 49.41 [cm3] and mean EAT density was -83.77 ± 15.48 [HU]. For female participants, EAT volume was 122.14 ± 34.63 [cm3] and mean EAT density was -89.55 ± 5.40 [HU].For all participants, mean EAT volume was 128.40 ± 47.14 [cm2].Echocardiographic datasets of diagnostic quality could be obtained for all patients. Mean LV ejection fraction for all patients was 60.72 ± 7.45 [%]. Measurements at height of the aortic valve, as seen in Global strain at the long axis for the endocardial layer was -20.98 ± 4.60 [%], -18.01 ± 3.87 [%] at the midmyocardial layer and -15.53 ± 3.38 (%) for the epicardial layer. Hence, averaged Global Longitudinal Strain (GLS) was -18.12 ± 3.90 [%]. Global strain at the short axis for the endocardial layer was -28.88 ± 8.01 (%), for the midmyocardial layer -18.56 ± 4.31 (%) and -12.14 ± 2.58 (%) for the epicardial layer. Therefore, mean Global Circumferential Strain (GCS) was -19.86 ± 4.55 [%]. Measurements at mitral valve for evaluating LV diastolic dysfunction are included in Weak correlation was found between EAT volume or density and E/é ratio  . Also, EAim of this study was to evaluate diagnostic capability of EAT in patients with mild-moderate AS with LVDD. But, our preliminary data could not establish a reliable connection between the degree of LVDD as assessed by echocardiography (goldstandard) and the amount of EAT as assessed by cardiac CT. Neither did EAT volume or density correlate with known marker of LVDD, i.e. E/e’ ratio, nor did it relate with Strain parameters GLS or GCS.As an inspiration for our study, recent preliminary data pointed towards a potential association between the amount of EAT and the presence of HFpEF  but withThis retrospective study measured EAT by cardiac MRI in short-axis slices using a commonly used cine technique , extended beyond the atrio-ventricular valves to cover the entire pericardium in endsystole and -diastole. Our CT examinations come as 3D dataset without gaps and a halved slice thickness compared to MRI. Therefore, CT based EAT reading claims to measure more accurately because of the improved epicardial coverage and image resolution and especially since the danger of erroneous inclusion of a pericardial effusion is not present in contrast to MRI examinations. Since EAT values are not changing during heart circle, differentiation between systole/diastole might not be necessary. The functional evaluation as provided by strain analysis via echocardiography (goldstandard) in our study provides comparable results to MRI, too. Myocardial deformation (strain) analysis showed abnormal values for GLS in about 30% of all patients with a cut-off value for GLS ≥ -16% based on existing literature , 25. A hEAT has been shown to produce pro-inflammatory and pro-atherogenic cytokines , 29, 30 In addition to that, Serrano-Ferrer et al. provides in individuals affected by metabolic syndrome a link between EAT and Strain . CavalcaFurthermore, within our rather small study population there were no significant differences between genders in association with EAT volume and cardiac function, which seems to be less important in this elderly cohort .However, we could not replicate the suspected correlations between LVDD and EAT in patients with AS, where increased volume and pressure loading seem to be more important driver of LV dysfunction rather than EAT volume alone. We conclude that major changes in EAT volume maybe are only present in advanced AS and HF with a reduced EF, and not in early valvular disease as was the case in our patient cohort . FurtherOur post-hoc study is supposed to be preliminary data and has several limitations: the use of tissue doppler imaging rather than speckle tracking echocardiography for strain rate imaging may have led to a greater variance of straining parameters due to noise and intra- and interobserver variability. Furthermore, our data was incomplete for longitudinal echo parameters and we could not supply any molecular biomarkers. Another aspect to keep in mind when looking at our results is the large proportion of men (84%) within our relatively small sample size (n = 50), in which significant coronary artery disease was not ruled out clinically. Since this is an elderly cohort, gender is statistically less important than age . The oneIn this preliminary study, epicardial adipose tissue volume as assessed by CT has no obvious influence on LVDD, as it does not correlate well with echocardiographic indices of LVDD as E/é ratio in patients affected by mild to moderate AS.S1 Table(PDF)Click here for additional data file.


Background: Heart failure is a pathophysiological state, which is still associated with high morbidity and mortality despite established therapies. Diverse well-known biomarkers fail to assess the variety of individual pathophysiology in the context of heart failure.Methods: An analysis of prospective, multimarker-specific therapeutic approaches to heart failure based on studies in current literature was performed. A total of 159 screened publications in the field of biomarkers in heart failure were hand-selected and found to be eligible for this study by a team of experts.Results: Established biomarkers of the inflammatory axis, matrix remodeling, fibrosis and oxidative stress axis, as well as potential therapeutic interventions were investigated. Interaction with end organs, such as cardio-hepatic, cardio-renal and cardio-gastrointestinal interactions show the complexity of the syndrome and could be of further therapeutic value. MicroRNAs are involved in a wide variety of physiologic and pathophysiologic processes in heart failure and could be useful in diagnostic as well as therapeutic setting.Conclusion: Based on our analysis by a biomarker-driven approach in heart failure therapy, patients could be treated more specifically in long term with a consideration of different aspects of heart failure. New studies evaluating a multimarker – based therapeutic approach could lead in a decrease in the morbidity and mortality of heart failure patients. Heart failure is a complex syndrome with major impact on public health. In the industrial world, about one out of ten persons over 65 years old is affected. Despite cardio-protective treatment with renin-angiotensin-aldosterone (RAAS) inhibitors, betablockers, neprilysin inhibitors and cardiac resynchronization therapy, mortality and hospitalization rates remain high . The widThe best-studied biomarker in heart failure is B-type natriuretic peptide (BNP), which is released in response to increased left ventricular (LV) filling pressures and wall stress. BNP is broadly used in the diagnosis of clinical heart failure . FurtherThe established biomarkers in heart failure fail to assess the variety of pathophysiological processes relevant to the condition of a heart failure patient see . Multi-mIn the following review, we present a prospective multi-marker-based therapeutic approach  to the mAn analysis of prospective, multimarker-specific therapeutic approaches to heart failure based on studies in current literature was performed. A total of 296 screened publications in the field of biomarkers in heart failure were screened and 159 were found to be eligible for this study due to the relevance of their contribution to this topic by a team of experts .The role of inflammation in heart failure has been proposed as levels of inflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6 were found to be elevated in heart failure. TNF and IL-6 serum levels correlate with heart failure severity and prognosis. Elevated basal cytokine levels might even predict future development of heart failure .Renal failure, arterial hypertension, chronic obstructive pulmonary disease (COPD), diabetes mellitus, metabolic syndrome and myocyte injury following myocardial infarction or viral infection are suspected to result in chronic inflammatory processes, which may contribute to the ten percent increase in heart failure incidence in the industrialized world . ConsequCRP represents a composite heart failure biomarker, which is a robust predictor of cardiovascular and non-cardiovascular mortality. Interestingly, an increased hsCRP was associated with a higher cardiovascular (CV) mortality irrespective of the baseline ejection fraction . Non-immConsequently, IL-1 β, as a biomarker and respective signal point with a potential of targeted heart failure therapy, is gaining attention. In animal models, a direct influence of IL-1β injection on systolic function was shown as well as on diastolic function . In acutHeart failure leads to sympathetic activation, which is coupled with an elevated pro-inflammatory cytokine profile. Given the evidence that the pro-inflammatory cytokine TNFα and soluble TNF receptors correlate with mortality in heart failure, it is thought that targeting this mediator may be beneficial in stopping heart failure deterioration . The ranin-vitro and in-vivo studies (Another interesting strategy is the application of intravenous immunoglobulin (IVIG) which proves to influence cytokine production in T-cells and monocyte/macrophage both in  studies , 28. In  studies .Cardiac remodeling is characterized by cellular and interstitial changes, usually in response to acute or chronic damage, consequently leading to changes in size, mass and function as well as geometry of the heart –33. In rHere, sST2, GDF-15 should be covered pars pro toto, as they represent some of the most established markers in the field. sST2 represents a marker predominantly used in the field of heart failure, where it was shown to independently predict mortality and hospitalization in acute or chronic heart failure , 37. TheThe cytokine GDF-15 is involved in the regulation of inflammation and fibrosis, and is expressed in most organ systems. Furthermore, GDF-15 is also involved in apoptotic processes. The secretion of GDF-15 is upregulated in response to organ damage. With respect to the cardiovascular system, GDF-15 induces cardio-protective effects through different cellular signaling pathways, interacting with ALK 1–7 and Smad-receptors, as well as the epidermal growth factor receptor (EGFR) and NF-κB/JNK/caspase-3 pathway . ElevateThus, when considering different pathophysiological processes involved in cardiac remodeling, such as inflammation, increased cardiac strain and oxidative stress, the novel cardiac biomarkers sST2 and GDF-15 are a promising for a more sophisticated assessment of cardiac remodeling . Their rMost etiologies of heart disease cause a pathological myocardial remodeling resulting in a cardiac fibrosis . In contTransforming Growth Factor β 1 (TGF-β1) is perhaps the most extensively studied biomarker of fibroblast activation and is known to have an impact on fibrotic processes in many organs. TGF-β1 is initially released in a complex with latent TGF-β binding proteins that inhibit its activity. It can be activated by proteolytic cleavage, and by binding to an activin receptor-like kinase (ALK 5), it is able to activate pro-fibrotic genes . This prIn the SOLSTICE Phase II trial, patients after a non – ST segment elevation myocardial infarction received the p38 inhibitor losmapimod without observation of major side effects. Although infarct size was non-significantly reduced, patients with intake of losmapimod experienced fewer cardiac events, such as heart failure. These findings provide hope for the therapeutic potential of losmapimod and resulted in the enrollment for the phase III LATITUDE-TIMI 60 trial. The primary endpoint, including a significant reduction of cardiovascular death, remained unmet, but in patients with a STEMI with higher age, elevated hs-CRP or chronic kidney disease, the risk of heart failure tended to be reduced , 63. FurOxidative stress is involved in the development and progression of heart failure. Oxidative stress is defined as dysregulation between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense mechanism system. ROS production is primarily caused by mitochondria, NADPH oxidases, xanthin oxidase and nitric oxide synthase, whereas the most important endogenous antioxidant defense mechanisms include superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), nicotinamide adenine dinucleotide (NAD+) and glutathione , resulting in the generation of oxidizing species , 68. In Furthermore, in a different prospective study evaluating in 412 patients with acute on chronic heart failure, the diagnostic accuracy of MPO could not be proven and showed no correlation with 1-year mortality .Small trials stated the beneficial effect on improved myocardial function, peripheral vasodilatation capacity, reduced BNP and increased LV ejection fraction. In a larger trial enrolling 405 patients, oxypurinol in general failed to improve the clinical status, but in the subset of patients with elevated uric acid, oxypurinol improved the symptoms of heart failure. This study highlights the need for a careful selection of patients potentially benefitting from anti-oxidative therapy.The more extensively studied antioxidative stress therapy in patients with heart failure is the inhibition of xanthin oxidase using allopurinol or oxypurinol. Uric acid, produced by xanthin oxidase (XO) and representative for the activation of the enzyme XO has pro- and antioxidant effects , 74. Sev2  is a thiol-containing antioxidant with the capacity to regenerate intracellular antioxidant pools. The NACIAM  trial, which examines the use of high dose NAC in combination with low-dose nitroglycerin in ST-segment elevation myocardial infarction patients after percutaneous coronary intervention, also demonstrated that the combined use of NAC and nitroglycerin might significantly lower infarct size and increase myocardial salvage with a consequent less severe following heart failure .Endogenous antioxidant therapy trials seem to have a promising future in the treatment of heart failure, but are still in an experimental phase .Since their discovery in 1993 by Lee et al. , microRNSeveral studies have investigated expressed miRNA concentrations in patients with acute and chronic heart failure –95. For Besides, miRNAs could also be useful in differentiating heart failure with preserved ejection fraction (HFpEF) from heart failure with reduced ejection fraction (HFrEF). Hence, Watson et al. recently found that serum levels of miR-30c, miR-221, miR-328, and miR-375 could adequately discriminate HFpEF from HFrEF, especially when combined with the plasma concentrations of BNP .In particular, miRNAs have a potential to distinguish heart failure of different etiologies and therefore, play an essential role on long term prognosis. Circulating levels of miR-423 and miR-34a were reported to be higher in patients with ischemic cardiomyopathy, whereas expression levels of miR-21-3p, miR-199 and miR-30a were rather elevated in the non-ischemic heart failure cohort. Furthermore, miR-423 is associated with a poorer prognosis in patients with acute HF .Similarly, miR-29a was found to be significantly upregulated in patients with hypertrophic cardiomyopathy  and it cHowever, miRNAs have not only been investigated for their diagnostic utility in various disease entities, including cardiovascular diseases. In fact, several miRNAs have already been applied therapeutically in different diseases in humans, for example in patients with hepatitis C virus (HCV) or oncological diseases , 102. ReInflammation and cardiac fibrosis are key features of cardiac remodeling, which is itself crucial for the pathogenesis and progression of HF. Recent evidence suggests, that inflammation and fibrosis are potentially reversible, rendering them interesting targets for novel therapeutic approaches in the management of HF. In fact, several miRNAs are known to interact with inflammatory, fibrotic and apoptotic pathways. For example, miR-21 was found to enhance myocardial fibrosis by targeting the extracellular signal-regulated kinase (ERK)–mitogen-activated protein (MAP) kinase pathway via sprouty homolog 1 (SPRY1)  and the Based on the findings of recent animal models, various miRNAs could represent attractive targets for innovative therapeutic approaches in patients with HF, for example silencing of miR-21 or substitution of miR-29b. In fact, several phase 1 and 2 trials are currently being conducted in humans, investigating the application of miRNA-based therapies . The mosApproximately 50% of patients with chronic heart failure have a chronic kidney disease (CKD) and 33–56% of HF patients have impaired renal function. CKD is associated with high mortality in patients with heart failure. Due to pathophysiological processes and interactions with each other, dysfunction of one organ may induce pathology in the other one . The mosImpairment of cardiac function may result in hepatic failure and vice versa. HF induces liver hypoperfusion and hepatic congestion. In cirrhotic cardiomyopathy, proinflammatory conditions cause cardiac injury and a shift in myosin heavy chain subtype a to the weaker b isoform . FurtherChronic heart failure induces a depletion of bacterial richness, in particular of butyrate-producing bacteria. Butyrate causes local anti-inflammatory effects in the intestinal mucosa and activates regulatory T cells . In patiNumerous studies evaluating tumor markers in heart failure have been conducted. To date, CA 125 seems to be the most promising. Several studies found a significant correlation between CA 125 and the different stages of heart failure in different populations, both in chronic and acute heart failure . Higher Myocardial expression of extracellular matrix osteopontin is associated with cardiac hypertrophy and is increased after development of heart failure , 135 in In vivo studies in knockout mice suggest a cardio-protective role of neuropilin, as the animals developed higher rates of cardiomyopathy and heart failure compared to the controls  originated from the bone marrow-derived cells have previously found as powerful endogenous contributor of vascular wall maintenance and the endothelium integrity . EPCs plThere is a large number of evidence of the fact that ARBs, ARNI, mineralocorticoid antagonists have yielded remarkable impact on the clinical outcomes among HFrEF and HFpEF patients through prevention of adverse cardiac remodeling and improving endothelial function in close connection with an increase in the viability and the number of circulating EPCs , 154. PeMulti-marker analysis can provide valuable information about the predominant processes in the complex, multifunctional and individual pathophysiology of heart failure. Biomarker-based therapy has the potential for providing prospective heart failure patients with tailored treatments adapted to the multi-faceted aspects of heart failure. Introduction of a new multi-marker-based therapeutic approach and resulting therapies as currently being investigated in clinical studies may offer new disease management options to potentially decrease the morbidity and mortality of HF patients.The lack of cardiac specifity is of major limitation. The variability of serum biomarkers is influenced by age, sex, co – morbidities and renal failure. Therefore, multimarker panels are recommended to improve prognostic utility.Intraindividual variation of serum marker is of further diagnostic limitation . EnvironAT, MM, BO, PJ, DF, MH, and AB performed literature research and prepared the manuscript. KK, LM, UH, AB, and ML revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Atrial fibrillation is the most prevalent supraventricular arrhythmia responsible for the large morbidity and mortality burden worldwide. There are various causes of atrial fibrillation that may affect the prognosis of patients. This study was intended to determine different echocardiographic findings in patients with atrial fibrillation in a tertiary care center.A descriptive cross-sectional study was conducted at Manmohan Cardiothoracic Vascular and Transplant Center, Institute of Medicine, among 175 patients with atrial fibrillation admitted in the cardiology department from June 2017 to October 2018. It was approved by the Institutional Review Board of the Institute of Medicine (Ref.:411(6-11-E)2/073/074). Convenience sampling was used. Statistical analysis was done using Statistical Package for Social Sciences version 21.0.A total of 175 patients with atrial fibrillation were enrolled where Rheumatic heart disease 68 (38.9%) was the leading cause in which 54 (79.4%) had mitral valve lesion, 1 (1.5%) had aortic valve lesion and rest had a combination of both. The mixed lesion of mitral stenosis and mitral regurgitation was the commonest. The left atrium size was larger in valvular atrial fibrillation (47.29±6.651mm). The left ventricular systolic dysfunction was seen more in non-valvular atrial fibrillation. The commonest site of thrombus formation was left atrium 7 (63.6%).Atrial fibrillation was common in rheumatic heart disease, especially mixed lesions of mitral stenosis and regurgitation. Valvular atrial fibrillation had a larger left atrium. The thrombus was seen in mitral stenosis and left ventricular systolic dysfunction. The left atrium size and left ventricular ejection fraction were associated with the occurrence of atrial fibrillation. All the patients with atrial fibrillation who presented to the department of cardiology were enrolled in the study. It was approved by the Institutional Review Board of the Institute of Medicine (Ref.: 411(6-11-E)2/073/074).The sample size was calculated using the formula:n = required sample sizeZ = 1.96 at 95% confidence intervalp = prevalenceq = 1-pe = margin of error, 5%Where,Adding a 10% non-responsive rate, the sample size was estimated to be 154. However, the total sample size taken was 175.With the written informed consent, a detailed history was taken, and a physical examination was done. Twelve-lead electrocardiography (ECG) was taken and transthoracic echocardiography with GE. Vivid seven was done to look for left atrium (LA) size, LVEF, and left ventricular wall thickness assessed in the parasternal long-axis view. The LA dimension of more than 40mm was considered dilated. The septal and posterior left ventricular wall was measured and considered abnormal if ≥10mm in females and ≥11mm in males. The LV function was calculated by M-mode or Simpson's method and was considered abnormal if below 55 percent; however severe LV systolic dysfunction was considered if LVEF was less than 30 percent. The valvular morphology, stenotic or regurgitant lesions, clots or any other defects were also noted. We used the Statistical Package for Social Sciences version 21.0 for statistical analysis. The data were presented in number and percentage. Categorical variables were reported as percentages. Continuous variables were reported as mean with standard deviation.Among 175 total patients with Atrial Fibrillation, the mean age of study patients was 60±16.79 years, ranging from 15 years to 92. Among valvular AF, the mean age was 47.9±14.013, and among non-valvular AF, it was 67.85±13.507 years. The female patients were predominant, i.e., 98 (56%) whereas 77 (44%) were male patients. The female patients seemed to suffer AF at an earlier age (57.17±17.84 years) than male patients (63.82±14.63 years).We found various etiologic factors of AF among which the majority 68 (38.9%) had Rheumatic heart disease, 29 (16.6%) had Dilated Cardiomyopathy (DCM), 10 (5.7%) had congenital heart disease , 13 (7.4%) had coronary artery disease (STEMI or NSTEMI), 5 (2.9%) had ischemic cardiomyopathy, 17 (9.7%) had hypertension only (in 16 patients hypertension was associated with other diseases), 16 (9.1%) had degenerative valvular heart disease (DVHD), 2 (1.1%) had mitral valve prolapse (MVP), 2 (1.1%) had hypertrophic cardiomyopathy, 8 (4.6%) had miscellaneous causes  and 5 (2.9%) were idiopathic.The patients with various etiologies presented to the hospital with varied causes mentioned in Among rheumatic valvular diseases, the mitral valve disease 54 (79.4%) was more associated with atrial fibrillation than aortic valve disease 1 (1.5%), the rest were both. The commonest was a mixed lesion of mitral stenosis and mitral regurgitation 23 (33.8%) followed by mitral stenosis 20 (29.4%) then mitral regurgitation 8 (11.8%). There were 10 (14.7%) patients who had only a mitral valve replaced (MVR), 1 (1.5%) patient had an only aortic valve replaced (AVR) and 6 (8.8%) patients had both the valves replaced. Four patients with aortic stenosis and three patients of aortic regurgitation were seen in combination with mitral valve lesions. The mitral regurgitation was seen in many other conditions in addition to rheumatic causes 27 (32.9%) such as DVHD 13 (15.8%), DCM 12 (14.6%), hypertension 10 (12.2%), coronary artery disease 8 (9.8%), ischemic cardiomyopathy 4 (4.9%), MVP 2 (2.5%) and other miscellaneous causes.The mean left atrium size in valvular AF was 47.29±6.651mm with a minimum LA diameter of 37mm and a maximum of 73mm. The mean left atrium size in nonvalvular AF was 42.20±4.356mm with a minimum of 33mm and a maximum of 59mm.Left ventricular hypertrophy (LVH) was observed in 19 (10.86%) patients. It was seen in conditions such as systemic hypertension, hypertrophic cardiomyopathy, aortic stenosis and ventricular septal defect.About 88 (50%) patients had normal LV function, while mild and moderate LV systolic dysfunction was present in 23 (13%) patients each and 41 (24%) had severe LV systolic dysfunction. There was more LV systolic dysfunction in the NVAF group than the valvular one. The median LA size and LVEF was higher in valvular AF group compared to non-valvular AF .Among total intracavitary clots, the mitral stenosis was associated with 64% of it, including a clot in the left atrium proper (37%) and both left atrium and left atrial appendage (27%). The patients with mitral valve replacement (9%), double valve replacement (9%) and acute coronary syndrome (9%) had left ventricular clot, and a case of dilated cardiomyopathy (9%) had left atrium and ventricular clot .The increase in the prevalence of atrial fibrillation and its significant consumption of health resources globally raises concern regarding the knowledge of multiple associated factors about its causation and consequences. Henceforth the various chief echocardiographic features associated with AF were studied in this study.13 The mitral valve disease caused a large left atrium and elevated left atrial pressure, which increases the dispersion of refractoriness and increased automaticity, creating the milieu for initiation and perpetuation of AF.14 The fibrosis and degeneration of the atrial myocardium in valvular heart disease, especially rheumatic etiology, disturb impulse propagation in the atria leading to AF that persists even after valve replacement or repair.16Rheumatic heart disease (38.9%) was seen as the commonest cause of atrial fibrillation. It was shown that among total rheumatic heart disease, rheumatic mitral valve disease (79.4%) was associated with AF more than other rheumatic valve diseases. The mitral regurgitation was seen in many conditions apart from RHD, such as dilated cardiomyopathy, ischemic cardiomyopathy, MVP, hypertrophic cardiomyopathy, degenerative valvular heart disease and myocardial infarction. But considering rheumatic valvular lesions, the mixed lesion of mitral stenosis and mitral regurgitation (33.8%) was commonest followed by mitral stenosis (29.4%) and then mitral regurgitation (11.8%). This finding was similar to a study done by Andrade et al.18 The LA enlargement was the echocardiographic parameter that was most associated with AF.11Our study showed the mean left atrium size was 47.3mm in valvular AF and 42.2mm in NVAF. The median LA size was higher in valvular AF than NVAF. The largest LA size was seen in severe rheumatic mitral regurgitation, which was 73mm. The finding was similar in some other studies.19The left ventricular hypertrophy was seen in 10.86% of patients. The prevalence of LVH was higher in patients with non-valvular AF, especially hypertension. The left ventricular hypertrophy leads to impaired left ventricular diastolic filling, increased left atrial pressure, left atrial enlargement, increased atrial fibrosis leading to increased atrial ectopic activity, and slowing of intra- and interatrial electrical conduction velocities.11The other parameter studied was left ventricular systolic function, which showed that about 50% of patients had LV systolic dysfunction, in which 26% had mild to moderate LV systolic dysfunction, and 24% had severe LV systolic dysfunction. Most of the LV systolic dysfunction was seen in patients with NVAF than valvular AF. It included patients mostly with DCM, ischemic cardiomyopathy, coronary artery disease and degenerative valvular diseases. A study revealed that a low LVEF was the second most associated parameter for the occurrence of AF.20 Another common site for thrombus formation was left ventricle which was seen in patients with LV systolic dysfunction in cases of dilated cardiomyopathy, acute coronary syndrome and mitral and double valve replacement due to reduced wall motion and stasis of blood in ventricle forming thrombus similar to the findings in a study done by Talle et al.21In our study, the clots were seen more in the left atrium and left atrial appendage in patients with mitral stenosis than mitral regurgitation as the high-velocity flow inside the left atrium in case of mitral regurgitation may prevent thrombus formation.There are some limitations to this study. This is a single-center study through a tertiary care super-specialty center. Some variables could not be considered, such as left ventricular diastolic function, left atrial volume. Rather a practically employed left atrial diameter was taken. Since transesophageal echocardiography wasn't possible in all cases, a left atrial appendage clot may have been missed in some cases.Rheumatic heart disease is the commonest cause of AF in developing countries. AF is commonly seen in mitral valve disease, in which mixed lesion of mitral stenosis and regurgitation is the most common. The left atrial size and left ventricular systolic dysfunction are the markers for the development of AF. The thrombus is seen in the left atrium in mitral stenosis and the left ventricle in cases with left ventricular systolic dysfunction.


Left ventricular assist devices (LVADs) are implantable mechanical devices that pump blood from the apex of the left ventricle to the aorta in order to assist the forward flow of blood; they are most commonly used as a bridge to transplant for patients with heart failure. As of February 2019, a total of 25,145 patients with ventricular assist devices have been reported in the Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs). As this number continues to grow, more and more of these patients will inevitably be seen in the acute care setting outside of their defined LVAD center. Currently, however, LVAD emergencies represent a high-acuity low-occurrence event with limited opportunities for exposure and mastery for most physicians. Therefore, a growing need exists for emergency care providers to familiarize themselves with these devices and the management of LVAD emergencies. We present a novel model for the simulation of LVAD emergencies created through simple modifications of a Laerdal 3G Manikin. The left ventricular assist device (LVAD) was initially developed in the 1960s as a bridge to cardiac transplant. Since the number of patients awaiting cardiac transplant has continued to rise, LVADs have also commonly become destination therapy. This device may also be used for temporary support in cardiomyopathies and patients diagnosed with New York Association’s class IV heart failure . PatientThe LVAD is composed of several key components that this simulator aims to mimic: the pump, which sits internally and pumps blood from the left ventricle into the thoracic aorta, the driveline, which is the percutaneous cable that exits the abdominal wall to connect the pump to the external components, an external computer controller, which both monitors and controls pump performance with a display screen, and a power supply, which typically rests along the patient’s hip with a backup battery located in an additional pouch .The LVAD pump provides continuous forward flow from the left ventricle to the aorta; as such there are notable physiological changes in these patients. There is no longer a definable systolic and diastolic component to the cardiac cycle. These patients will lack a palpable pulse, and healthcare providers will not be able to record a traditional blood pressure . This loThis simulation was built with a Laerdal 3G Manikin ; however, other manikin models may be used in its place. The following steps and figures serve to outline the simple process of configuring an LVAD simulator.A small square of manikin-colored material should be cut approximate to the size of your intended window dressing; for this model, a Sorbaview 2000 window dressing  was used with a window of approximately 4 x 4 cm. Red grease paint and modeling clay were used for creating a moulage, representing erythema with mild bleeding as seen in Figure A Bardex 20-French silicone Foley catheter  was used to represent the driveline coming from the patient’s abdomen and connecting to the controller. The Foley catheter Figure .A discarded PositionPro hospital bed remote  was then used as the patient controller with a printed image modeled after a Heartmate III controller  Figure . The FolTwo large squared batteries, taken from an Audio-Technica wireless microphone receiver , were then placed in the waist packs from a hiking backpack Figure  to repreThe Sorbaview 2000 window dressing piece was then adhered to the right mid-abdomen with the Foley catheter portion feeding out laterally connecting to the simulated controller Figure . The driFinally, an electric toothbrush was placed in the manikin’s chest cavity and turned on to represent the LVAD pump functioning within the heart, creating the continuous hum that would be heard when auscultating these patients Figure .The number of patients with LVADs will continue to grow and will inevitably come under the care of healthcare providers unfamiliar with LVADs. Patients with LVADs have frequent ED visits and subsequent admissions with a wide array of emergent complications . These eWith only minor modifications, simulation centers can create a functioning LVAD simulator that can be incorporated into their simulation curriculum. The Brooke Army Medical Center (BAMC) Simulation Department has successfully incorporated this simulator into training for the BAMC Emergency Medicine Residency with cases including ventricular fibrillation, driveline bleeding, and surgical site infection.The basic modifications outlined in this article allow for the creation of a high-fidelity low-cost LVAD simulator that can be used to provide familiarity with LVAD physiology and education on the complex pathology unique to these patients. The model is both reusable and can be reverted back to the manikin’s original state with relative ease.


Sickle cell disease (SCD) is an inherited disorder that occurs due to point mutation in the beta-globin chain resulting in the production of hemoglobin S that tends to become rigid and sickle-shaped under low oxygen concentration. These sickle-shaped red blood cells (RBCs) obstruct the blood vessels leading to reduced blood flow to the organs, causing ischemia and tissue fibrosis. These sickle RBCs being abnormal in shape are frequently sequestered by the spleen, creating a state of chronic anemia in the body. This chronic anemia leads to a high cardiac output state causing cardiac remodeling. To tackle chronic anemia, patients are frequently treated with blood transfusions that makes them more prone to the risk of iron overload (from newly transfused RBCs and iron release from the RBCs that just got sequestered as well as from volume overload) and volume overload causing left ventricular (LV) dilation. The above-mentioned mechanism of cardiac hypertrophy, along with LV dilation together, makes SCD-related cardiomyopathy unique cardiomyopathy with features of restrictive cardiomyopathy with LV dilation. It is interesting to note here that even though there is a presence of LV dilatation, Systolic dysfunction is very uncommon in SCD-related cardiomyopathy. Complications of sickle cell disease (SCD) represent the significant health care burden in developed countries and cardiovascular (CV) complications being the highest causes of mortality . SCD is Chronic inflammation in SCDChronic inflammation has been said to play an essential role in the pathogenesis of SCD, reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells being its important component . Human aPathophysiology of SCD-related cardiomyopathy and its complicationsSCD, which originated from Sub-Saharan Africa, Southeast Asia and India, has been known to be the most common inherited hemoglobinopathy worldwide due to increasing migration in the modern world. Prolonged exposure to high cardiac output state from chronic anemia in SCD leads to significant dilatation of LV which, over time, adapts to increased wall stress by developing eccentric LV hypertrophy, as shown in Figure Myocardial fibrosis in SCDIntravascular hemolysis causing nitric scavenging, along with repeated vaso-occlusion by sickle RBC can contribute to microvascular dysfunction, which has been identified to cause cardiac dysfunction in SCD patients Figure  9,10]. ,10. 9,10Myocardial iron overload uncommon in SCDChronic blood transfusion-related iron overload cardiomyopathy is a major cause of death in patients with chronic anemia, such as in thalassemia or SCD . High moDiastolic dysfunction in SCDMany studies identified diastolic dysfunction in SCD as an independent risk factor for premature death -20. FactPulmonary hypertension in SCDPathophysiology of pulmonary hypertension (PH) in SCD is complex and is a significant cause of mortality and morbidity in patients -25. A stPreventive measures to cope with complicationsBy diluting the load of sickle red blood cells in the circulation, chronic blood transfusion may reduce the risk of vaso-occlusion and stroke . HoweverThis study was conducted to demonstrate the pathophysiology of cardiomyopathy occurring in patients with SCD. It aimed to study the cause behind the restrictive nature of SCD-related cardiomyopathy and the impact of chronic anemia on the heart and its long-term complications in patients. It was very interesting to note that the patients who had diastolic dysfunction did not have myocyte iron overload, as confirmed by CMR, which means iron overload was not the cause of restrictive cardiomyopathy in patients. Instead, it occurs due to myocardial fibrosis from vaso-occlusion as well as from ventricular hypertrophy caused by chronic anemia. This restrictive cardiomyopathy, along with LV dilation from the hyperdynamic state in the body together, makes SCD-related cardiomyopathy unique cardiomyopathy. This paper is crucial as it explains the complicated nature of cardiomyopathy related to SCD, which will help clinicians to understand the pathophysiology of SCD-related cardiomyopathy and will help them with treatment plans for patients. It will also help to educate patients about their disease. During our literature search, we realized that even though frequent transfusions are required to treat chronic anemia and to dilute sickle cells in the blood, it has its side effects too. We encourage future researchers to study the consequences of frequent transfusions in order to lay down strict guidelines for its early management and prevent various complications arising from volume overload.


Mechanical prosthetic aortic and mitral valves preclude either a retrograde aortic or transseptal approach to the left ventricular (LV) endocardium. Several operators have reported on the application of nonconventional techniques for ventricular tachycardia (VT) ablation including transventricular septal puncture, epicardial approach, transmechanical valve approach, transcoronary venous approach, and transapical approach. Incorporating transventricular access to the LV under intracardiac echocardiography (ICE) guidance has been previously attempted in VT ablation procedures in patients with both aortic and mitral mechanical valves. However, while ICE is readily used in the United States, its use is less common in Europe, since the health insurance agencies largely do not cover the costs of ICE catheters. We therefore herein present a case of VT ablation in the LV using a transventricular approach in a patient who underwent mechanical double valve replacement performed under subcostal echocardiographic and fluoroscopic guidance. Several operators have reported previously on the use of nonconventional techniques during ventricular tachycardia (VT) ablation such as transventricular septal puncture, and 2, the interventricular septum was crossed with a Brockenbrough needle under uninterrupted warfarin and intravenous heparin therapy. It was difficult to dilate and advance the aforementioned Swartz™ Braided SL1 sheath  from the transventricular septum; however, the catheter manipulation was easy to perform after the crossing was complete. The three different VTs originating from the LV apical and posterobasal regions were induced  and late potential substrate ablation during sinus rhythm and the areas of the middiastolic potentials during VT  and 2C were ablated. In total, the procedure lasted about 5.3 hours without intraprocedural complications or residual ventricular septal defect . He recovered uneventfully and experienced one VT episode that responded to antitachycardia pacing therapy one day later. He was discharged five days after the procedure with heart failure therapy  and mexiletine. At present, this patient is being followed up with in the outpatient clinic.A 69-year-old male patient with nonischemic dilated cardiomyopathy was referred for VT ablation due to electrical storm. He had a history of double valve replacement and biventricular pacemaker implantation. Since his documented VT morphologies were compatible with the LV posterobasal and apical regions, we chose to perform transventricular crossing, as it was thought that it could be potentially difficult to reach all parts of the LV apex using transapical access. The right internal jugular vein was accessed, and a Swartz™ Braided SL1 Transseptal Guiding Introducer Sheath  was advanced to the basal right ventricular septum. We preemptively prepared the Amplatzer™ Muscular Ventricular Septal Defect Occluder device  as a bailout plan for use if there was a catastrophic septal defect at the time of removal. After confirming there was a safe distance from the coronary septal perforator branches with both left and right coronary angiography and no entrapment of the tricuspid septal leaflet by subcostal echocardiography 8 Although epicardial VT ablation is a potentially useful method in patients with mechanical aortic and mitral valves,9 the coronary venous system approach6 or transventricular septal access2 have additionally been applied successfully in certain patient populations. Yamada et al.10 and Herweg et al.5 reported the successful ablation of LV VTs via a transseptal approach and the crossing of a mechanical mitral valve prosthesis.5 In the latter study, a recurrence of monomorphic VT at two months later required a second VT ablation procedure using the same transseptal–transmitral approach.5 Transventricular septal access to the LV has been also reported in transcatheter aortic valve implantation procedures under intracardiac echocardiography (ICE) guidance.11 The use of ICE during transventricular septal puncture has been recommended from the viewpoint of safety; however, while it is generally used in the United States, it is not common in Europe, as health insurance agencies do not cover the costs of ICE catheters. Subcostal echocardiography was particularly useful for the confirmation of no entrapment of the tricuspid septal leaflet at the transventricular access point in the current case. Coronary angiography should be performed to assess the presence of large septal coronary artery perforators at the region of the midinterventricular septum, where safe access could be attempted.1 Transventricular access by subcostal echocardiographic guidance may be considered as an alternative route, particularly in critically ill patients when conventional percutaneous transaortic or transmitral valve access approaches are not possible.12In patients with mechanical double valve replacement and VT, catheter ablation may be prevented by limited access to the LV. However, direct access to the LV cavity by way of a percutaneous LV apical puncture through the intercostal space overlying the apex or through a left minithoracotomy or left lateral thoracotomy is a viable option for the mapping and ablation of LV VTs.


Echocardiographic reference intervals for Friesian horses are poorly described.To obtain reference intervals for echocardiographic measurements in Friesians and compare these with Warmbloods.One hundred healthy adult Friesians and 100 healthy adult Warmblood horses.t test with Bonferroni correction for multiple comparisons.Cross‐sectional study. Two‐dimensional and M‐mode echocardiographic images were obtained. Echocardiographic measurements, including size, area, and volumetric measurements of left atrium, left and right ventricle, aorta, and pulmonary artery, were performed. Measurements were compared between the 2 breeds using an independent samples CI] = −245 to −63). Also the right ventricular end‐diastolic and peak‐systolic internal diameter were smaller in Friesians . Fractional shortening (99.85% CI = 0.61‐6) and ejection fraction (99.85% CI = 0.21‐4.6) were significantly larger. No structural effects of systemic hypertension, such as concentric hypertrophy, were detected.Reference ranges for standard echocardiographic measurements in Friesians were obtained. Several left ventricular measurements were significantly smaller in Friesians compared to Warmbloods, such as the left ventricular end‐diastolic volume using the 4‐chamber modified Simpsons' method (99.85% confidence interval for the difference [Our study provides reference intervals for echocardiographic measurements in Friesians useful in a clinical setting. In general, the left ventricular dimensions in Friesians were significantly smaller compared to Warmbloods, emphasizing the need for breed‐specific reference intervals. Standardized echocardiographic images and measurements are established,The Friesian breed is marked by considerable inbreeding, which presumably has contributed to their distinctive conformation and higher prevalence of several diseases.Friesians react differently with training22.1A cross‐sectional study was performed. The study sample consisted of 100 healthy adult Friesians aged (median [range]) 10 [3‐26] years and 100 healthy adult Warmbloods aged 8 [3‐25] years. The Friesians consisted of 72 mares, 23 geldings, and 5 stallions and the Warmbloods of 61 mares, 35 geldings, and 4 stallions. Whether the horse was in training, as opposed to at rest in the field, at the time of the study (yes/no) was registered, as well as information about pregnancy and lactation. Mares over 6 months of gestation or within 1 week after parturition were excluded. In all horses, auscultation, echocardiography, and ECG were performed. Inclusion criteria were: no more than a 2/6 left‐ or right‐sided systolic or diastolic murmur on auscultation, no more than mild valvular regurgitation visible with Doppler ultrasound examination, and absence of atrial and ventricular premature beats during a 15 minutes ECG recording at rest. Height at the withers, body length, and chest circumference were measured for every horse. Body length was determined from the most cranial point of the shoulder to the tuber ischiadicum, chest circumference was measured right behind the elbow. Body weight was estimated using the following formula2.2Echocardiography was performed in the standing, nonsedated horse . A 1.5 to 4.6 MHz phased array probe (M5Sc‐RS) was used at a frequency of 1.7/3.3 MHz with simultaneous ECG recording (base‐apex). Two‐dimensional images included the right‐parasternal long‐axis 4‐chamber view (4C) and the right‐parasternal long‐axis view of the left ventricular outflow tract (LVOT). M‐mode images were obtained of the right‐parasternal short‐axis view of the left ventricle (LV) at the chordal level.2.3end, LADmaxsend, LADdend, LADmaxdend), the LA area at end‐systole and end‐diastole (LAAsend and LAAdend),end, LVLsend, LVAdend, LVLdend).peak, AoDdend, PADspeak, and PADdend)peak/AoDspeak). The M‐mode variables, measured at the chordal level, included the right ventricular (RV) internal diameter at peak systole and end‐diastole (RVIDspeak and RVIDdend), the interventricular septal thickness at peak systole and end‐diastole (IVSspeak and IVSdend), the LV internal diameter at peak systole and end‐diastole (LVIDspeak and LVIDdend), and the LV free wall thickness at peak systole and end‐diastole (LVFWspeak and LVFWdend).end) were calculated using the following formulasAll images were blinded for breed and analyzed by a single observer, using dedicated software . The mean of 3 consecutive cycles was used for further analysis. Cycles following a second‐degree atrioventricular or sinoatrial block were not used for analysis, and resulted in analysis of 3 nonconsecutive cycles in some cases. Three nonconsecutive cycles were also used when image quality was inadequate to obtain 3 consecutive cycles. Heart rate (HR) was determined as the mean of 3 RR intervals of the 3 consecutive cycles on the 4C view. Images were only recorded and analyzed if HR was below 50 beats/min. The measurements on the 4C view included the left atrial (LA) diameter at the mitral valve annulus and at maximal dimension parallel to the mitral valve annulus at end‐systole and end‐diastole (LADsVolumetric measurements of the LV (LVV) were performed with built‐in algorithms using 2 different methods: (a) the 4C area‐length method and (b) the 4C modified Simpson's method, both based on the measurements performed on the 4C view.Using the 4C modified Simpson's method, the LVV is calculated as:4C‐ALsend, LVV4C‐ALdend, LVV4C‐MODsend, LVV4C‐MODdend). The stroke volume was calculated as the difference of the end‐diastolic and end‐systolic volume , and the ejection fraction as the ratio of the stroke volume over the corresponding end‐diastolic volume .The LVV was determined at end‐systole and end‐diastole using each method  were calculated for the lower and upper limits,t tests were performed for each variable and Bonferroni correction was performed to correct for multiple comparisons. The overall significance level was P < .05. For each variable, P values were considered significant if P < .002 (= 0.05/34 variables) and 99.85% CI for the mean difference were calculated.Data analysis was performed using dedicated software . Variables were tested for normality by analyzing the Q‐Q plots. Normally distributed data are presented as mean ± SD and nonparametric data as median [range]. Categorical data are presented as proportions. The homogeneity of variances was tested with the Levene's test. Age was compared between the 2 breeds using a Mann‐Whitney 3P < .001) while the chest circumference  and body length  were significantly larger in Friesians. Friesians also had a significantly higher estimated BW . Significantly more Friesians were in training (P < .001) or pregnant (P = .006). No difference could be detected between the breeds for age (P = .29), HR (P = .43), sex (P = .24), or lactation (P = .07).Summary statistics of the study sample are given in Table end. Of the LA dimensions, only the LADsend was significantly smaller in Friesians compared to Warmbloods. Apart from a smaller AoDspeak, the dimensions of the aorta and pulmonary artery were not significantly different between the 2 breeds. The IVSdend was significantly smaller in Friesians, on the other hand, the IVSspeak was significantly larger in Friesians. The functional indices FS and the EF4C‐MOD were significantly higher in the Friesians compared to the Warmbloods. No significant difference could be found for the EF4C‐AL.The echocardiographic measurements and their reference intervals are displayed in Tables 4In our study, echocardiographic dimensions between Friesians and Warmbloods of similar age and sex were compared. This analysis demonstrated that in general the LV and the right ventricular internal diameter of a Friesian were smaller compared to that of a Warmblood and that the functional indices were generally higher in Friesians. Next to breed, other factors might have influenced these differences, such as training level, body conformation, and pregnancy.4C‐MOD might be explained by the fact that a smaller LV in a body of approximately the same size needs to increase its systolic function to preserve sufficient stroke volume.end and higher IVSspeak in Friesians, despite a similar longitudinal systolic shortening of the LV (data not presented), might be explained by the shorter LV in Friesians which could affect myocardial fiber orientation, left ventricular systolic shape, or M‐mode cursor positioning. For some variables, the differences might be accounted for by the expected between day and within observer variability for echocardiographic measurements. Nevertheless, several clinically relevant differences, namely the LV size, the functional indices, and the right ventricular internal diameter, were found, emphasizing that breed influences should be taken into account when interpreting echocardiographic measurements.The higher FS and the EFend, LV mass, RWT and MWTdend, and decreased ejection fraction and FS.VO2max), is linked to LV size.The influence of breed might be difficult to distinguish from effects of sport discipline and training level.The significantly lower height at the withers of Friesians might also explain the smaller LV size and right ventricular internal diameter apart from breed‐specific influences. However, height at the withers is less correlated to echocardiographic measurements than chest circumference,In humans, changes in LV geometry are a predictor of systemic hypertension as well as a consequence of systemic hypertension.More Friesians in our study were pregnant. Pregnancy induces several hemodynamic and cardiovascular changes in humans, such as an increased HR, increased cardiac output, mild general cardiac dilatation, increased LV and RV mass, and increased LV wall thickness.A limitation of our study was the quality of the echocardiographic images. Due to the body conformation of Friesian horses, echocardiography can be challenging.Authors declare no conflict of interest.Authors declare no off‐label use of antimicrobials.The current study (EC 2018/11) was performed following the guidelines of the Ethical Committee of the Faculty of Veterinary Medicine, Ghent University, Belgium.Authors declare human ethics approval was not needed for this study.