Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF. Cardiomyocyte transverse tubule (t-tubule) microdomains organized by the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1) have recently emerged as a master regulator of beat-to-beat myocardial contraction and relaxation. Not only are cBIN1-microdomains critical to normal cardiomyocyte biology and heart physiology, they are also remodeling in diseased cardiomyocytes. Abnormal remodeling in cBIN1-microdomains is a common pathophysiology of acquired heart failure. In this review, we will summarize the current knowledge of t-tubule cBIN1-microdomains regarding their formation, function, regulation, and turnover, as well as their potential as heart failure biomarkers and therapeutic targets.Cardiac t-tubules are sarcolemmal invaginations which form a dynamic membrane system important for excitation–contraction (EC) coupling via its role in organizing ion channels and other membrane proteins critical to the intracellular process of calcium-induced calcium release (CICR). In cardiomyocytes, t-tubules form a complex network comprising approximately 21 to 64% of the total sarcolemma  together with β2 adrenergic receptors, facilitating channel modulation during sympathetic stress . AnkyrinFormation—Cardiomyocyte cBIN1-microdomains are created by t-tubule membrane microfolds sculpted by a membrane curvature formation protein cBIN1. BIN1 (amphiphysin 2) is an N-terminal Bin1-Amphiphysin-Rvs (N-BAR) domain-containing protein that is widely expressed . BIN1 waBin1 produces 4–6 transcript variants and the corresponding protein isoforms. The two cardiac characteristic isoforms feature the inclusion of exon 13 (deficient of exons 14–16) with or without the ubiquitously alternatively spliced exon 17 to form the protein isoforms of BIN1+13 and BIN1+13+17  . Th. Th35]. CS, a new blood test for heart failure—Given their significance in sustaining optimal intra-myocyte beat-to-beat calcium transients, cBIN1-microdomains at t-tubules are emerging as a crucial regulator of myocardial function as well as a promoter of heart failure progression when disrupted. In heart failure, both stress-induced transcriptional reduction and abnormal splicing cause reduced cBIN1 protein expression, disrupting cBIN1 microdomains and promoting disease progression. Furthermore, due to the homeostatic release of extracellular cBIN1-microvesicles, the amount of cardiac t-tubule cBIN1-microdomains correlates to the level of cBIN1-vesicles in circulation. As a result, plasma cBIN1 levels are direct indicators of the amount of myocardial t-tubule cBIN1-microdomains, reflecting a stable functional reserve of cardiomyocytes . Thus, qA cBIN1-specific blood test can provide an accurate measurement of myocardial functional reserve in symptomatically stable patients, and thus provide a potential biomarker of myocardial health and reserve. A cBIN1 blood test has already been developed and explored for clinical usage in aiding heart failure management. In a previous study using a clinical cohort of arrhythmogenic right ventricular cardiomyopathy, low plasma BIN1 measured by an ELISA test identified patients developing symptomatic heart failure and predicted future arrhythmia incidences . HoweverThis newly developed cBIN1 ELISA assay has been successfully used to obtain plasma cBIN1 concentrations from hundreds of healthy control patients without heart failure. These original data indicate that the log transformation of plasma cBIN1 levels in a healthy population follows a normal distribution . To simpCS performance in heart failure diagnosis and prognosis—The performance of CS in facilitating heart failure diagnosis and prognosis was tested in two clinical cohorts of heart failure including patients with heart failure with reduced (HFrEF)  and presBased on the data from the HFpEF cohort , a partiCS and heart failure early diagnosis—More recently, we identified that cBIN1 reduction occurs in early cardiomyocyte t-tubule remodeling before myocardial functional decompensation and symptomatic heart failure . AssayinHeart failure is a major and fast-growing public health problem affecting over 6 million Americans and 2% of the adult population worldwide ,62. EvenThe pathophysiological hallmark of a failing heart is abnormal calcium handling ,71,72. ASERCA2a—The first and most extensively studied strategy aimed to overexpress SERCA2a in failing hearts based on the observation that both the level and activity of SERCA2a are downregulated in human and experimental models of heart failure. Investigators succeeded in reversing cardiac dysfunction in isolated human cardiomyocytes , murine Adenylate cyclase 6—Another approach proposed to treat heart failure involves the manipulation of β-adrenergic signaling. Adenylate cyclase 6 (AC6) catalyzes ATP to cAMP, a key factor that is generated in response to β-adrenergic receptor stimulation and activates PKA. Preclinical studies on a swine model of heart failure proved AC6 gene transfer improved cardiac function and attenuated deleterious left ventricular remodeling ,87. The I-1c—An additional alternative method of gene therapy for heart failure relies upon overexpressing the constitutively active inhibitor I-1c that binds and inhibits PP1. Inhibited PP1 leads to increased PLN phosphorylation and improved SERCA2a activity, which ultimately restores normal calcium flux and β-adrenergic stimulation. In a preclinical swine model of myocardial infarction-induced heart failure, the overexpression of I-1c by intracoronary administration of an AAV9 vector preserved cardiac function and reduced scar size . A new cDespite promising results in animal models, clinical trials of gene therapy for heart failure have not yet shown positive results. Several possible explanations for the inconsistency between the preclinical and clinical studies are: (1) low efficiency of gene delivery to cardiomyocytes: improper viral vectors, inadequate delivery methods, sub-optimal dose, etc.; (2) inappropriate animal models: inadequacy of a preclinical animal model in fully mimicking human heart failure, limited available models of heart failure in large animals; (3) wrong therapeutic target gene: insufficiency to alter failing cardiomyocytes by introducing a targeted gene . TherefoThere is a major unmet need for effective target genes for treating heart failure. Due to the complexity of heart failure etiology and the diversity of clinical manifestations in heart failure patients, a master regulator that acts on multiple proteins and cellular pathways might be better positioned to drive the functional recovery of failing muscle. Unlike many other heart failure-associated molecules, cBIN1 creates t-tubule membrane microdomains which are involved in the multilayered regulation of calcium flux. Thus, targeting cBIN1-microdomains provides a unique opportunity to protect inotropy and lusitropy simultaneously via the effective organization of the entire calcium regulatory machinery from the systolic calcium-releasing unit dyads to the key diastolic calcium remover SERCA2a.The therapeutic effect of cBIN1 gene therapy has been tested in two mouse models of hypertrophy and/or heart failure. The study by Liu et al.  investigcBIN1 gene therapy as a potential treatment for heart failure in the future. Further studies in large animals with common heart failure comorbidities will be needed before clinical trials can be pursed. Additionally, more efficient and higher cardiac-tropic methods of delivering the cBIN1 gene will need to be explored. Overall, cBIN1 is a promising new target for the development of therapeutic tools for treating heart failure, and persistent effort in developing and testing cBIN1 gene therapies will reveal its full therapeutic potential.Taken together, here we have highlighted the current preclinical animal experiments that support the use of In this review, we provide an overview of the current understanding of t-tubule cBIN1-microdomains and their alterations in heart failure. Cardiomyocyte t-tubule cBIN1-microdomains are a master regulator of intra-myocyte calcium handling and a marker and therapeutic target of heart failure and thus deserve further investigations at the bench and the bedside. Future preclinical studies in large animal models as well as clinical trials in human patients will be needed to further test the biomarker potential of the plasma CS test as well as the therapeutic potential of targeting cBIN1-microdomains in failing cardiomyocytes.


To develop technical recommendations on the acquisition and post-processing of renal longitudinal (T1) and transverse (T2) relaxation time mapping. A multidisciplinary panel consisting of 18 experts in the field of renal T1 and T2 mapping participated in a consensus project, which was initiated by the European Cooperation in Science and Technology Action PARENCHIMA CA16103. Consensus recommendations were formulated using a two-step modified Delphi method. The first survey consisted of 56 items on T1 mapping, of which 4 reached the pre-defined consensus threshold of 75% or higher. The second survey was expanded to include both T1 and T2 mapping, and consisted of 54 items of which 32 reached consensus. Recommendations based were formulated on hardware, patient preparation, acquisition, analysis and reporting. Consensus-based technical recommendations for renal T1 and T2 mapping were formulated. However, there was considerable lack of consensus for renal T1 and particularly renal T2 mapping, to some extent surprising considering the long history of relaxometry in MRI, highlighting key knowledge gaps that require further work. This paper should be regarded as a first step in a long-term evidence-based iterative process towards ever increasing harmonization of scan protocols across sites, to ultimately facilitate clinical implementation.The online version of this article (10.1007/s10334-019-00797-5) contains supplementary material, which is available to authorized users. There is an increasing need for the development of non-invasive imaging biomarkers to assess the influence of fibrosis and inflammation in the kidney. Renal disease often progresses unnoticed and clinical measurements such as estimated glomerular filtration rate (eGFR) and albuminuria tend to deteriorate late in the disease course. The application of MRI for non-invasive tissue characterization by voxel-wise mapping of longitudinal T1) and transverse (T2) relaxation time of the kidney without contrast media, referred to as native T1 and T2 mapping, is a promising tool for predicting clinical outcomes in parenchymal renal disease and providing guidance in clinical decision-making. T1 and T2 relaxation times can be indicative of alterations in tissue composition such as fibrosis, oedema or cyst progression  and tran. The abihttps://renalmri.org) was established to share best practice and realize the full potential of renal MRI biomarkers. As part of the COST Action PARENCHIMA initiative a systematic review on T1 and T2 mapping was performed which indicated the lack of agreement in patient preparation, acquisition protocols and adequate patient selection, as well as widely accepted reference values . Little is known about the influence of hydration state on T1 or T2 values of the kidney; however, cardiac T1 mapping has shown that fluid overload significantly prolongs native T1 . Higher field strength provides increased signal-to-noise ratio and greater dynamic range of T1 values, but conversely, there are greater field inhomogeneities and a shortened T2 dynamic range. The system-integrated body coil should be used for RF transmission and multichannel receivers are recommended when performing T1 and T2 mapping of the kidney [R 2b], as implemented in cardiac and liver imaging.Validation studies on renal T1/T2 mapping have been performed both at 1.5 and 3T, with recent multi-parametric studies being performed more frequently at 3T . T1 and [R 3a]. This decision was reached as this is currently the only scheme that is widely available across MR vendors, with a 5(3)3 MOLLI scheme being an acceptable scheme [R 5b]. When a MOLLI scheme is chosen, a fixed spacing of 1 s is recommended as opposed to ECG triggering [R 5c-d], as ECG triggering is not applicable to the kidney in contrast to cardiac imaging. Despite the MOLLI scheme being only a single slice method, this was agreed to be sufficient [R 5e] and should be collected in a breath hold of less than 15 s to be useful in patients that might be compromised in their ability to hold their breath for longer durations [R 5f]. 10 of the 17 experts  also recommended a classic inversion recovery based scheme comprising at least 10 different TIs [R 4b]. A VFA method is not recommended, only 20% of the panel felt this scheme is suitable for native T1 mapping.For T1 mapping, a consensus was reached to recommend a Look-Locker variant (for example MOLLI) The ultimate choice of T1 mapping scheme depends on the goal of the study. At the current time, MOLLI will provide an appropriate choice for a large multicenter study comprising a multiparametric protocol, since it is widely available and fast. However, for a single-center study aimed to detect subtle changes in tissue microstructure, one might choose the classical inversion recovery sequence (with or without slice cycling) which has been shown to be more precise over a wide range of T1 values .T2 prep scheme, though not widely available, yields highly reproducible T2 measurements independent of scanner type and manufacturer, as shown for myocardial T2 mapping  and that the maximum echo time should be at least equal to the T2 of the kidney (e.g. approximately 120 ms at 3T) [R 6b].A consensus was reached that at least five T2 weightings should be acquired for accurate T2 estimation In general, for a multiparametric scan protocol, it might be necessary, or at least convenient for data analysis and interrogation, to use the same readout for all acquisitions. In particular for T1 mapping and ASL, we recommend using the same readout, since the T1 maps can be used in the perfusion quantification .[R 5a], as this flip angle results in the highest signal-to-noise ratio. For classical inversion recovery, an EPI readout is recommended [R 4a]. No consensus was reached for T2 mapping.For MOLLI, a single-shot balanced gradient echo/balanced steady-state free precession (bSSFP) readout with a flip angle of 35° is recommended [R 3b] to assess differences between cortex and medulla while maintaining signal-to-noise ratio. For T1 mapping, a maximum slice thickness of 5 mm is recommended , but for T2 mapping, no consensus was reached. Regarding field of view and matrix size, no consensus was reached. For classical inversion recovery with an EPI readout, left–right phase encoding direction, as is typical for abdominal imaging, is recommended. A parallel imaging factor of 2 is recommended for T1 mapping readout schemes to yield high SNR, artifact-free maps.Regarding spatial resolution, a minimal in-plane resolution of 3 mm is recommended [R 3f] as this orientation provides information about the distribution of T1 or T2 values in different anatomical areas of the kidney; upper pole, interpolar region, and lower pole. Furthermore, in this orientation, respiratory motion is in-plane and through plane motion is limited, enabling effective respiratory correction through registration. In contrast, for an axial acquisition, a given slice may be located at different levels in the kidney due to respiratory motion in free breathing acquisitions or inconsistent breath holds between multislice images.A coronal or axial plane can be used to image both kidneys in the same field-of-view during one acquisition. However, a coronal or coronal oblique orientation  is preferred [R 7a]. A B1 map can be beneficial for confirming good field homogeneity [R 7b], though the need for a B1 map to correct for the readout flip angle (e.g. to ensure the exact flip angle is used in MOLLI scheme) is still debatable. Limitations of additional B0/B1 mapping increasing the technical complexity to the scan protocol were raised. For the MOLLI scheme, a consensus was reached that T1 values should be quantified using a three-parameter curve fit (Eq. [1d]) [R 7c].With regard to T1 quantification, a consensus was reached that inversion factor correction is not required [R 8a]. However, the expert panel considered automated ROIs to be preferred over manual ROIs [R 8c]. For protocols that acquire multiple slices of the kidney in the same orientation, it is recommended to combine all ROIs across all slices [R 8b] to reach a more balanced estimate of the ROI measurement. No consensus was reached on whether single or multiple ROIs in the cortex or medulla be used, or on the need for taking ROI size into account when using multiple ROIs.For image analysis, the expert panel considered manual ROI selection of the medulla and cortex to be an acceptable analysis method at this moment [R 9a]. In addition, T1 and T2 values should be reported as either mean with corresponding standard deviation or median with interquartile range (depending on the distribution of the data). Suggested measures to reflect corticomedullary differentiation are both the T1 cortex medulla difference (T1 medulla—T1 cortex) [R 9b] and the corticomedullary ratio (T1 cortex/T1 medulla) [R 9c]. It is recommended to report the number of cases with no visible corticomedullary differentiation, as this limits the determination of separate relaxation times for renal cortex and medulla [R 9d].Several recommendations were made by the expert panel with regard to the reporting of T1 and T2 mapping results. In subjects with visible corticomedullary differentiation, relaxation times should be provided for cortex and medulla separately No T2 mapping sequence  reached consensus. In addition, no consensus was reached with regard to a minimum matrix size for renal T1 and T2 mapping schemes. Noting that for an EPI acquisition, the minimum achievable echo time is dependent on the matrix size and acceleration factor used, it is suggested that a minimum field of view of 320 mm × 320 mm be considered to ensure a reasonable echo time for classic IR T1 mapping. With regard to adopting methods to minimize off-resonance effects to avoid banding artifacts in MOLLI variants of T1 mapping, 53% of the panel had insufficient experience to make a recommendation so no consensus was reached. To provide some guidelines, B0 shimming and centre frequency can be adjusted to minimize off-resonance. This is especially important at higher field strengths where off-resonance effects can result in regional variations in apparent T1 . If avai2 in representative areas of both cortex and medulla; ROIs in upper pole, interpolar, lower pole region of both kidneys; and one ROI including, respectively, the cortex or medulla as a whole. In addition, it was highlighted that studies on the reproducibility of manual ROI measurement of renal T1 and T2 mapping are needed. For automated ROI analysis, no specific strategy resulted from the questionnaire. Automated ROI analysis strategies mentioned by the expert panel included a visual distribution approach (e.g. k-means clustering), and histogram analysis to differentiate between cortex and medulla. Furthermore, it was highlighted that heterogeneity in the distribution of T1/T2 values across the kidney may be useful for assessing the presence and progression of CKD.Although consensus was reached that manual ROI analysis of the renal cortex and medulla is acceptable, no specific strategy was decided upon from the following strategies: one large ROI parallel to the outer edge of the cortex; at least three ROIs of > 0.1 cmn = 18), which can be considered a shortcoming of this work. However, it included scientists from groups that have all developed or applied renal T1 mapping applications. The proportion of technically oriented panel members was high, justified by the current state of development of the technique. Other limitations include differences in the level of detail in the provided recommendations as these are inherent to the maturity of the research field. As such, provided recommendation on data analysis and reporting include semi-automated approaches, and the influence of fitting routines, defining of outliers, handling of missing slice data, and the associated penitential bias for estimated T1 and T2 have not been addressed. Several knowledge gaps are highlighted based on the results of this survey. More research is needed on possible factors influencing renal T1 and T2 measurements such as hydration state, fasting state, salt intake or medication use, with hydration state being of great interest as volume regulation can be affected in renal patient populations. Despite reaching consensus on the 5(3)3 MOLLI scheme for renal T1 mapping, this scheme has been optimized for cardiac T1 mapping and its use is in part driven by its availability across all major MR vendors, rather than its optimization for measurement of renal T1 values, leaving room for further improvement. Furthermore, the use of a 5(3)3 MOLLI scheme can be limited with respect to spatial resolution, since each of the 5,3,3 single-shot images must occur within a 1 s interval. High spatial resolution MOLLI data can be achieved through the use of segmented multi-shot data acquisitions, assuming each breath-hold is consistent. Likewise, it should be noted that a classic IR with single-shot EPI acquisition is also limited in achievable spatial resolution due to the increased echo time at higher spatial resolution.The panel of experts that participated in this consensus formation process was of limited size 3 schemes , 42, 43,Technical recommendations were constructed to incorporate the opinions and advice of a multidisciplinary group on renal T1 and T2 mapping. These highlight the current lack of consensus in both renal T1 and T2 mapping, to some extent surprising considering the long history of relaxometry in MRI, highlighting key knowledge gaps that require further work. Given the dynamic nature of physiological imaging methods in terms of data acquisition and analysis, we expect and encourage detailed studies to systematically compare renal T1 and T2 mapping methods, and validate methods against reference standards for inter-site studies, and harmonize approaches across vendors. This paper should be regarded as a first step in a long-term evidence-based iterative process towards ever increasing harmonization of scan protocols across sites. These outcomes should inform periodic updates of these recommendations on renal T1 and T2 mapping. The panel will stay in existence and recommendations will be revisited and updated as and when new evidence becomes available.Supplementary material 1 (DOCX 30 kb)Supplementary material 2 (DOCX 22 kb)Below is the link to the electronic supplementary material.


Evaluation of tissue fibrosis and myocardial hypertrophy in left ventricular (LV) remodeling is the basis of post-treatment evaluation of hypertensive heart disease (HHD). Extracellular volume (ECV) and myocardial strain parameters can indirectly reflect the changes of both. Our objective was to analyze the characteristics of ECV and strain parameters in LV myocardium of HHD with varying degrees of systolic dysfunction, and to explore the changes of both after treatment for hypertension.A total of 62 HHD patients were divided into 3 groups according to ejection fraction . Twenty-one of these patients underwent cardiac magnetic resonance (CMR) reexamination more than six months after receiving antihypertensive medication. The initial T1 time and post-enhancement T1 time of each segment were measured, and the ECV was calculated. Radial strain (RS), circumferential strain (CS) and longitudinal strain (LS) of LV were measured by cvi42 software, and the differences in CMR parameters between different groups and before and after treatment were compared.P < 0.05), but the difference between HHD groups was not statistically significant. ②With the decrease of EF, the absolute value of both the global or local strain decreased. Strain is related to LVMI and ECV. ③In general, ECV, global RS (GRS) and global CS (GCS) improved after treatment, but the improvement of LS impairment in HHD patients is difficult.①The mean, basal and middle ECV value of HHD groups with different EF were all higher than that of the control group (ECV and myocardial strain parameters are more sensitive to myocardial abnormalities, and ECV, GRS and GCS are more sensitive to treatment. However it is difficult to improve longitudinal strain impairment in HHD patients. ECV and myocardial strain parameters can be used as good makers for long-term monitoring of the efficacy of HHD patients. HHD is a structural and functional abnormality of the heart caused by a long-term increase in systemic circulating arterial pressure. Its pathophysiological basis is cardiac remodeling, which including the development of left ventricular hypertrophy (LVH) and diffuse interstitial fibrosis . LVH is Multiple studies have shown that hypertension medication can reverse LVH , 9, but 2 in men,> 61 g/m2 in women . T1MyoPre, T1MyoPost, T1BloodPre, T1BloodPost were the T1 measurements performed in myocardium and blood before and after contrast enhancement, respectively. Hematocrit was obtained by routine hematological examination of the patient. EDWT was obtained by measuring the wall thickness of left ventricular segments 1–16 at end diastole .All strain parameters and conventional cardiac function parameters were obtained using the commercial post-processing software cvi42 . Cine image series acquired in short-axis and four-chamber long-axis orientations were imported into the 3D module of the software. Cine image series acquired in short-axis, two-chamber long-axis and four-chamber long-axis orientations were imported into the Tissue Tracking module of the software. Endocardium and epicardium tissue contours were drawn semi-automatically, and left and right ventricle boundary points were marked manually. Based upon the demarcations of LV, myocardial strain parameters were calculated via the cvi42 software package including: 2D and 3D RS, CS, and LS. Conventional cardiac function parameters were also calculated including LVEDVI, LVESVI, LVSVI, and LVMI. T1 values of the heart muscle and blood pool before and after enhancement were obtained from the inline T1 map generated by the MOLLI sequence. According to the LV 17-segment analysis method developed by the American Heart Association, the initial T1 time and post-enhancement T1 time of each segment were measured, and the mean T1 values before and after enhancement of segments 1–6 , segments 7–12 (middle segment), and segments 13–16  were calculated. The ECV values of the LV basal segment, central segment and apex segment and the overall ECV values were calculated according to the following formula: ECV = (1-hematocrit) × [. All continuous data were expressed as mean ± standard, and one-way analysis of variance (ANOVA) was used for multiple comparisons. Data that did not conform to a normal distribution were expressed as median and inter-quartile range with two-sided non-parametric test used for multiple comparisons. The CMR data acquired from patients before and after drug treatment were compared using a paired-sample t-test or non-parametric test of related samples if data did not conform to a normal distribution. Pearson correlation or Spearman correlation coefficients were calculated to evaluate the relationship between different parameters . In this study, 62 HHD patients were enrolled and divided into 3 groups according to their EF. Among them, 22 patients in the group had an EF less than 30%, 18 patients had an EF greater than or equal to 30% and less than 50%, and 22 patients had an EF greater than 50%. Among these patients, 21 patients underwent CMR re-examination after taking antihypertensive drugs for more than 6 months. The antihypertensive drugs were either ACEI or ARB drugs. For these patients, after antihypertensive drug treatment, blood pressure was controlled to within 130–110/90–70 for twice consecutive observations. Table P < 0.05), but there was no significant difference among HHD groups. There was no significant difference of the ECV value in apical myocardium among the groups.Representative CMR images and T1 maps used for ECV calculations are shown in Fig. P < 0.01). After the exception of the GRS parameter, there was no significant difference in HHD in the EF≧50% group and the control group (P < 0.01). There were significant differences of the global and local CS and LS between the EF < 50% group and the EF≧50% group.Comparisons between global and local myocardial strain values in the different groups are shown in Table When comparing all HHD patients, EF demonstrated a significant correlation with GRS, GCS, and GLS strain parameters Fig. . The coeEF and GRS is the biggest in patient groups with EF < 50%; however, GLS has the greatest effect on EF for the largest slope. In patient groups with EF ≧ 50%, GCS has a larger slope and a larger correlation coefficient than that of GRS and GLS. Across all the subjects, global strain parameters demonstrated a relatively weak correlation to ECV Fig. a. A stroP = 0.02), lower LVEDV (P = 0.03), EDWT (P = 0.03), and mean ECV (P < 0.001). The RS of global and middle segment and the absolute value of the basal and global CS were all increased (P < 0.05). The differences among LVEDVI, LVSVI, LVMI, and LS were not statistically significant  and sympathetic nervous system (SNS) is greater than LVH regression by lowering blood pressure alone . ACEI anThe current study has some limitations. First of all, the sample size is small, so the sample may not accurately reflect the overall situation. Secondly, there is no grouping based on the choice of treatment drugs, so different types of antihypertensive drugs may have different therapeutic effects, and CMR parameters may also change differently. Thirdly, patients were not followed up for cardiac adverse events after treatment, and the combination of changes in related parameters with prognosis may be more meaningful for guiding clinical treatment. In addition, molecular, biomechanical and structural changes in HHD after treatment may take a longer time. Hence, the changes of the study metrics may be more significant had the study duration been prolonged.ECV and myocardial strain parameters for myocardial abnormalities are more sensitive. ECV, GRS and GCS are more sensitivity to treatment than other parameters, however the improvement of GLS in patients with HHD is weak. ECV and myocardial strain parameters can be used as CMR marker for long-term monitoring of the curative effect of patients with HHD.


Extracorporeal life support provides perfusion for patients with heart failure to allow time for recovery, function as a bridge for patients to heart transplantation, or serve as destination therapy for long term mechanical device support. Several biomarkers have been employed in attempt to predict these outcomes, but it remains to be determined which are suitable to guide clinical practice relevant to extracorporeal life support. Galectin-3 and soluble suppression of tumorigenicity-2 (sST2) are two of the more promising candidates with the greatest supporting evidence. In this review, we address the similarities and differences between galectin-3 and sST2 for prognostic prediction in adults and children with heart failure requiring extracorporeal life support and highlight the significant lack of progress in pediatric biomarker discovery and utilization. Heart failure is a life-threatening condition in both adults and children and is associated with high mortality, morbidity and cost of care. The incidence of heart failure in the general population is 2000/100,000 in adults . ExtracoN-acetyllactosamine (LacNAc)-containing glycoproteins, and the only known one with a single carbohydrate recognition domain and a unique N-terminus [Galectin-3 is a member of the galectins family of carbohydrate-binding proteins with specificity for terminus ,20. It iterminus . It is mterminus ,23,24,25terminus ,27. Evidterminus , congeniterminus  and survterminus . In additerminus ,32,33,34terminus .VAD implantation is a standard ECLS modality for adult patients with end-staged heart failure. A retrospective study  includinp < 0.001). The increased galectin-3 concentration is associated with the severity of heart failure and can be reduced by spironolactone treatment [There is significantly less literature regarding galectin-3 in pediatric patients as compared to adults. Similar to adults, the galectin-3 concentration has been reported to be higher in children (median age: 9 years) with chronic heart failure than those (median age: 8.5 years) with normal heart function  glycoprotein that is a member of the interleukin 1 receptor family. The ST2 glycoprotein is encoded by the IL1RL1 gene located in the chromosome 2q12. It serves as the receptor for IL-33, an IL-1–like cytokine that can be secreted by living cells in response to cell damage . IL-33 esST2 has been much less studied in ECLS than galactin-3. One study by Tseng et al.  showed tAs described above, galectin-3 and sST2 have been used alone or concomitantly as biomarkers in several studies regarding heart failure with or without ECLS ,31,46. GData regarding the similarities and differences of galectin-3 and sST2 between adults and children at baseline and while undergoing ECLS are extremely limited. To date, only one study  is availTo the best of our knowledge, no data are available to describe the trend and prognostic value of plasma or serum galectin-3 and sST2 in children or adults undergoing VA-ECMO for cardiac failure. VA-ECMO use is much more common in pediatric patients than VAD implantation compared to adults, and this deficit requires further studies to fill this gap of our knowledge.The general principles to evaluate feasibility of a biomarker include the following: (a) it is easily obtained, (b) highly reproducible, (c) it is biologically plausible and (d) impacts care. Obtaining a blood sample is part of the postoperative routine and does not involve technically complicated procedures. The measurement of plasma or serum galectin-3 and sST2 would not be a significant burden to a current clinical protocol. Second, a biomarker should be scientifically reproducible and financially affordable. The assays for human plasma/serum galectin-3 and sST2 have been commercially available for clinical and research purposes . The staUnlike the traditional biomarkers including natriuretic peptides and troponins, sST2 is relatively independent from age, prior diagnosis of HF, body mass index, ischemic type of HF, or atrial fibrillation ; galectiNatriuretic peptide-guided therapy in chronic heart failure has been reported in some studies with promising outcomes ,57,58, wAs described in sST2 concentrations have been used to identify patients with chronic heart failure who may particularly benefit from β-adrenergic blocker therapy . At cutoIn terms of a targeted therapy on sST2 itself, no chemical compound serving as a sST2 antagonist has been reported. Instead, an anti-ST2 mAb has been used to block the interaction between sST2 and IL33 to release free IL33 . The conNeither galectin-3 and/or sST2 has been examined as guides for adjusting medical management for heart failure in pediatric patients, and thus the role of galectin-3 and /or sST2 as a guide to therapeutic decision-making remains to be established. Additionally, within the pediatric patient population, the use of galectin-3 and/or sST2 as a biomarker for risk stratification in children undergoing ECLS with VAD has not been reported, and the impact of VA-ECMO on galectin-3 and sST2 remains unknown.Undergoing ECLS creates a complex clinical situation with challenges related to early and accurate prediction of prognosis, particularly in pediatric patients. To distinguish patients who will improve and those who will not early during ECLS is imperative as would not only assist the medical team to formulate an optimal care plan but may also provide a scientific justification to initiate ethical discussions with the patient’s family. Galectin-3 and sST2 have come to prominence as early prognosticators in adult ECLS patients since other biomarkers , and biomarker response to other forms of ECLS (such as VA-ECMO) that may serve to improve the care of the pediatric patient population.


The aim of this study was to establish a feasible and robust magnetic resonance imaging protocol for the quantitative assessment of cardiac function in marmosets and to present normal values of cardiac function across different ages from young adult, middle-aged, to very old clinically healthy animals. Cardiac MRI of 33 anesthetized marmosets at the age of 2–15 years was performed at 9.4 T using IntraGate-FLASH that operates without any ECG-triggering and breath holding. Normalized to post-mortem heart weight, the left ventricular end-diastolic volume (LV-EDV) was significantly reduced in older marmosets. The LV end-systolic volume (LV-ESV) and the LV stroke volume (LV-SV) showed a similar trend while the LV ejection fraction (LV-EF) and wall thickening remained unchanged. Similar observations were made for the right ventricle. Moreover, the total ventricular myocardial volume was lower in older monkeys while no significant difference in heart weight was found. In conclusion, IntraGate-FLASH allowed for quantification of left ventricular cardiac function but seems to underestimate the volumes of the right ventricle. Although less strong and without significant sex differences, the observed age related changes were similar to previously reported findings in humans supporting marmosets as a model system for age related cardiovascular human diseases. Callithrix jacchus), has become increasingly popular in preclinical biomedical research, not least because of the recent advantages in generating transgenic marmoset offspring2. Marmosets have been extensively used as a model system for studying reproduction, infectious diseases, brain functions and aging6. Moreover, obesity and diabetes, two common risk factors for cardiovascular diseases in humans, have been intensively explored in marmosets10. Using radionuclide angiography, Charnock et al.11 showed that nutrition high in dietary fat can significantly influence the composition of cardiac membranes towards increased level of fatty acids. In addition, those marmosets showed an increased heart rate together with an increased left ventricular ejection fraction.In the recent years a small New World non-human primate (NHP), the common marmoset  is currently one of the main imaging techniques for the assessment of cardiac function and morphology in human. Recently, cardiovascular MRI has also been successfully used in macaques16, particular advantages of the marmoset model in aging research is a relatively short generation time, small size and availability of genetically modified models. Several groups have shown age-related changes in the pathology of common marmosets but have focused mainly on the central nervous system7. Two post-mortem studies looking for the cause of death in two large colonies showed a significant higher prevalence of cardiac fibrosis in aged marmosets17, but only little is known about the consequences of increased age on cardiac function in this species.In our rapidly aging societies, suitable animal models most closely resembling human aging are urgently required. Besides similarity to humans and other NHPsThe aim of this work was to establish a robust and feasible MRI protocol to measure the cardiac function of marmosets and to present average values of cardiac function across clinically healthy animals of different ages ranging from young adults (2 years) up to very old marmosets (15 years). Difficulties of, and possible solutions for, carrying out cardiovascular MRI of marmosets will be discussed.Short-axis images were acquired during free breathing using a navigator based IntraGate-FLASH. The quality of the data sets was investigated by visual inspection and blinded rated using a 5 point-score . Based on that 4 out of 33 animals were excluded from further data analysis due to a score lower 3 . In addition, one data set had to be excluded due to a circumscribed signal loss in region of the right ventricle. The quality score of all included animals was on average 4.5 ± 0.6 (range: 3–5). Figure Parts of these artefacts had their origin in a corrupted navigator signal as illustrated in Fig. The cardiac rates observed under anesthesia were in the range of 150 and 250 bpm. Fluctuations of this rate throughout data acquisition led to widespread peaks in the frequency domain  and as a result to a clearly reduced image quality. Similarly, additional signal fluctuations  led to an insufficient image quality. A lack of rhythmic signal fluctuations  resulted in no visible ventricular contraction on the reconstructed dynamic images. Consequently, these corruptions of the navigator signal led to an exclusion of the data sets and may be used in future for automatic quality control.Changes of the signal intensity related to respiratory movement could be detected on all navigator signal curves. Due to the respiratory frequency given by the artificial ventilation frequency analyses revealed always a sharp peak around 35 bpm. In addition, in most of the cases harmonics of the respiration were visible at multiples of 35 bpm.Figure All marmosets were grouped by age into three groups for further analyses (young adult (<5 years), middle-aged (5–9 years), and senescent (>9 years). The respective group compositions as well as mean values of heart rate, body weight, and post-mortem heart weight are shown in Table The weight of the hearts, measured post-mortem and including ventricles and atria, ranged from 1.85 g to 3.13 g . This weight was positively correlated with the body weight of the animal  and the ventricle myocardial volume measured by MRI  and became particular evident when normalizing the myocardial volume by the respective post-mortem heart weight Fig. . This inThe stroke volume (SV) of the left ventricle averaged over all analyzed marmosets was 427 ± 107 μl in total and corresponded to 1.05 ± 0.23 μl/g body weight. The mean respective end-diastolic volume (EDV) and end-systolic volume (ESV) were 755 ± 142 μL and 328 ± 67 μL resulting in an average ejection fraction (EF) of 56 ± 7% (range: 41.5–69.0%). Using absolute values one-way ANOVA revealed no significant age effect for none of the acquired parameters of left ventricle function . However, when correcting for the weight of the heart Table  the EDV The EF was, as expected, positively correlated with the absolute and fractional wall thickening . However, in all 29 animals included, a very good delineation of the cardiac wall and a sufficient visualization of papillary and trabecular muscles were achieved.Utilizing a navigator based IntraGate Flash sequence, a method that has been used so far mainly in rodents14 and humans21. In contrast to humans, in whom on average the mass and size of the heart is lower in women compared to men20, male and female marmosets showed comparable heart weights. Together with the similarity in body weight between sexes, this observation extend the finding that marmosets, in contrast to most other primates, exhibit no somatic sex-dimorphism, neither externally nor internally. Based on that, we pooled the data of both sexes together. More detailed analysis of subtle sex differences may require a larger number of marmosets per group.The volume of the ventricular myocardium and likewise the post-mortem heart weight were significantly correlated with the body weight of the marmoset. The average LV-SV of 1.05 ± 0.2 μl/g body weight corresponds to what has been reported in macaques20. In addition, Maceira and colleges22 reported a reduction of the LV-ESV in elderly people. Between the age of about 20 to 80 years volume reductions were likewise found for the right ventricle including EDV, ESV, and SV23.Aging is a main risk factor for cardiovascular diseases. A variety of studies investigated the effect of age on cardiac anatomy and function in humans. The Multi-Ethnic Study of Atherosclerosis (MESA), for instance, that investigated men and women between the age 45 and 84 and free of cardiovascular diseases, revealed progressively reduced EDV and SV in older age whereas EF remained almost unchanged17 and increased blood pressure25 with increasing age in marmoset, we observed only relatively mild disturbances of the cardiac function with age.Taking an average life expectancy of about 12 years for marmosets in captivity, the age range of the marmosets included in this study corresponds to about 18 to 80 years in humans. Even though previous studies have reported higher risk of myocardial fibrosis20, this reduction in ventricular volumes did not lead to a reduction of EF or wall thickening. Both, EF and wall thickening remained preserved in elderly marmoset, at least under rest. Another parameter that has been put into the context of aging is the left ventricular mass (LVM). It is defined as the volume of the myocardial muscle multiplied by 1.0526. Follow up measurements in humans revealed an increase in LVM with age in men and a mild decrease in women. Cross sectional, however, the LVM was decreased in elderly asymptomatic humans of both sexes21. The latter is very much in line with our observations in marmosets. Moreover, since we also know the post-mortem heart mass of these animals, it became clear that this reduction of myocardial volume went along with an increase in tissue density by about 23% (group 1 versus group 3). Thus, the assumption of a fixed muscle density in order to calculate the LVM is misleading and it may be more advisable to use the ventricular muscle volume (LV-MV) instead.In particular, the absolute values of the left ventricular volume showed no significant age effect but a relatively large variation between the animals. To compensate for physiological variations in human these values are commonly reported normalized to BSA or metabolic body weight. None of these normalizations changed the result in our marmoset study significantly. Interestingly, however, when correcting for post-mortem heart weight, all left ventricle volumes showed a tendency of reduction with age, with EDV reaching the level of significance. In addition, the EDV and ESV of the right ventricle were reduced with age, reaching the level of significance already for the absolute values. Likewise previously reported for humansThe observed changes in myocardial density fit nicely to reports on cardiac histopathology in marmosets and humans showing that tissue remodeling and diffuse interstitial fibrosis are main characteristics in cardiac life course. Future MRI studies should certainly utilize fibrosis sensitive techniques including gadolinium enhanced MRI and mapping of T1 relaxivity, which may in particular help to unravel the time course of tissue remodeling in follow up studies.28. The reasons for that discrepancy are most likely of technical nature. In particular, the oblique orientation of the tricuspid valve compared to the mitral valve which is usually used to align the short-axis view, hampers a correct detection of the atrio-ventricular valve plane of the right ventricle. Because of this a precise determination of the right ventricle volume is a well-known challenge in cardiac MRI and the method applied in this study does not seem to master this challenge. This systematic error makes it impossible to determine the exact absolute RV volumes. Interestingly, however, the difference between left and right SV was independent of age (p = 0.97). Thus, cautiously drawing conclusions about the relative differences obtained from the marmosets within the study may still be appropriate.A limitation of this study became apparent by the lower stroke volumes for the right ventricle compared to the left. Under physiological condition, these volumes should of course be similar. Differences in LV-SV and RV-SV, however, have been reported by several MRI studiesImprovements for future studies should certainly include the use of multichannel-coils. Parallel imaging techniques can then be used to speed up the acquisition. The relatively long scan time was one of the main sources for the observed image artefacts. Moreover, a better spatial resolution including thinner slices will certainly help to reduce the underestimation of the RV-SV in future studies. In addition, more complex navigator techniques which allow the detection of arrhythmias may increase the success rate of the data acquisition. Further development will include the usage of non-Cartesian k-space techniques like radial or spiral trajectories to increase the spatiotemporal resolution and to reduce respiratory artifacts.16 and the recent achievements in genetic manipulation of these monkeys2, these findings strongly support marmosets for the use as model system for age related cardiovascular diseases.In conclusion, the observed age related changes in marmoset were rather similar to previously reported findings in clinically healthy humans although to a lower extent. These changes involved a reduction of the ventricular volumes with increase in age while cardiac efficiency largely remained unaffected. Remodeling processes of the myocardium seem already to occur in middle aged marmosets including a reduction of myocardial volume by increased tissue density. Taking into account the cardiovascular similarities that share marmosets with humansCallithrix jacchus) with an age ranging from two to 15 years (7.4 ± 3.8 years) and an average weight of 408 ± 46 g. The study cohort consisted of 15 females and 14 males. The animals were grouped by age as follow: young adult (<5 years), middle-aged (5–9 years), and senescent (>9 years)29.Experiments were conducted on 33 adult, clinically healthy common marmoset monkeys , 5.3–8.8 years (middle-aged), and 9.1–14 years (senescent).All animals were raised and kept in accordance with the German Animal Welfare Act. All experiments were carried out with the approval of the ethics committee of the Lower Saxony State Office for Consumer Protection and Food Safety (33.19–42502–04–17–2496) and in accordance to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.Marmosets were initially anesthetized with a mixture of alfaxalone  and diazepam . This was followed by 0.05 ml glycopyrronium bromide  per animal to prevent secretion, maropitant  as an antiemetic, and meloxicam  as anti-inflammatory analgesic. Anesthesia was maintained with 0.9 ± 0.3% isoflurane in a mixture of oxygen and ambient air as required. Marmosets were mechanically ventilated via an endotracheal tube for the duration of the measurement (respiration rate = 35 bpm). The body temperature was kept constant by blankets filled with warm water. Physiological parameters, such as rectal temperature, heart rate, chest movement and peripheral arterial oxygen saturation were continuously monitored during experimentation .In order to perform MRI anesthetized marmosets were positioned in the sphinx position in a custom-made MRI-compatible stereotaxic frame to minimize movement artifacts. The ear bars served additionally as hearing protection and were dabbed with a lidocain containing ointment  for local anesthesia. Application of eye ointment  prevented the eyes from drying out during anesthesia.At the end of the study animals were deeply anaesthetized with a combination of ketamine , xylazine  and atropine  followed by an intraperitoneal administration of pentobarbital (150–200 mg/kg). A broad spectrum of organs including the heart was collected for further analyses.Cardiovascular MRI were obtained on a 9.4 Tesla small animal MRI-system  equipped with a 330 mT/m gradient system . A custom made ellipsoid single-loop receive coil with a diameter of 38 mm × 35 mm  was positioned underneath the chest for optimal coverage of the heart.3) ECG-gated T1-weighted images were obtained during free breathing covering the heart in three orientations . To quantify the cardiac function, short-axis images were acquired during free breathing using a navigator based IntraGate-FLASH sequence with following parameters: 40 navigator points, repetition time (TR) = 48 ms, echo time (TE) = 2 ms, flip angle = 12°, Field of View (FOV) = 55 × 55 mm2, acquisition bandwidth = 85 kHz, echo position = 33.33%, spatial resolution = 0.215 × 0.215 × 1 mm3, 2 × 2 in-plane interpolation, slice gap = 1.5 mm, 5 slices (from apex to base) and 200 repetitions resulting in a total acquisition time of approximately 23 minutes.For slice positioning, low-resolution  and the end-systolic volume (ESV) were calculated using Simpson’s method of disks31. The stroke volume (SV) and the ejection fraction (EF) were defined as the difference between EDV and ESV and the relation of SV and EDV, respectively. The myocardial volumes (MV) of the left and right ventricle (excluding the atria) were defined as the volume difference of the corresponding epicardial and endocardial volumes of the ventricles. The total ventricular myocardial volume (TV-MV) was defined as the sum of LV-MV and RV-MV. The left ventricular diastolic/systolic wall thickening , absolute wall thickening  and the fractional wall thickening  were calculated using a six sector bullseye of the three mid-ventricular slices. The six sectors were defined as anterior, anteroseptal, inferoseptal, inferior, inferolateral, and anterolateral 34. The apparent myocardial tissue density was defined as the ratio of post-mortem heart weight and the total ventricular myocardial volume measured by MRI.To compensate for the heterogeneous size of the animals, following parameters were used to normalize the volumetric parameter: the post-mortem heart weight (HW), the body weight (BW), and the body surface area (BSA). The latter was calculated according to the equation proposed for macaquesAll values reported are given as arithmetic mean ± standard deviation. Statistical analysis was performed using Matlab . Unless otherwise stated one-way ANOVA with post hoc t-test was used to calculate significant age differences between the groups. A value of P < 0.05 was considered as statistically significant, because this is the first explorative study on the topic we did not adjust for multiple testing.Supplementary Information.


A total of 42 AWHF patients from the CATSTAT-HF study were stratified in two groups by the RV FWS median (−16.5%). Patients < RV FWS median had significantly prolonged international normalized ratio , increased total bilirubin (p < 0.001) and alkaline phosphatase , and decreased albumin (p = 0.005) and thrombocytes (p = 0.017) compared to patients > RV FWS median. RV FWS independently correlated to total bilirubin , ALP , INR , albumin , and thrombocytes . Similarly, TAPSE, RV FAC, and RV S′ significantly correlated with RV FWS. In conclusion, RV impairment, reflected in reduced RV FWS, is independently associated with a higher degree of hepatic dysfunction among patients with AWHF .Right ventricular (RV) function is an important predictor of prognosis in patients with heart failure. However, the relationship of the RV free wall longitudinal strain (RV FWS) and the degree of hepatic dysfunction during the acute worsening of heart failure (AWHF) is unknown. We sought to determine associations of RV FWS with laboratory liver function tests and parameters of RV function including tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV FAC), maximal tricuspid jet velocity (TR V The ability of right ventricle (RV) to maintain forward cardiac output and prevent systemic venous congestion in the setting of left-sided heart failure (HF) due to systolic and/or diastolic dysfunction becomes an essential determinant of clinical outcomes . PreviouRV dysfunction and HF, in general, are commonly associated with impaired hepatic function while HF and liver disease often coexist . CardiohOn the other hand, RV free wall longitudinal strain (RV FWS) has recently emerged as a speckle-tracking echocardiographic method providing a feasible and reproducible measure of RV systolic function and its mechanics . RV has Since RV dysfunction in HF has been implicated in hepatic derangements, we hypothesized that impaired RV systolic function, as reflected in the reduced RV FWS, would adversely affect biochemical parameters of liver function. Of note, the relationship of RV FWS with hepatic function in general and also among patients with HF has been unexplored thus far. Therefore, in the present study, we sought to measure RV FWS, as the indicator of RV function, among patients with acute worsening of chronic HF (AWHF) and in the absence of significant primary liver disease or acute liver injury. Our main objective was to determine the potential association of RV FWS with laboratory LFTs in this patient cohort. Of secondary importance was to determine the association of RV FWS with traditional parameters of RV function and estimated pulmonary artery pressures.We consecutively included a total of 42 patients  in the study of which all have completed advanced deformation imaging via speckle-tracking echocardiography including the analysis of 2D right ventricular free wall strain (2D RV FWS) and left ventricular global longitudinal strain (LV GLS) along with standard transthoracic echocardiography (TTE) examination. Patients were recruited from the original CATSTAT-HF study of which baseline patient characteristics, study design, and inclusion/exclusion criteria are described elsewhere in detail . A studyIn short, in this echo substudy, we consecutively enrolled patients of both sexes with acute worsening (decompensation) of chronic HF that were in New York Heart Association (NYHA) functional class II–IV. All patients had a previously verified and documented history of HF. None of the patients had NT-proBNP levels < 300 pg/mL (“rule-out” criteria) and all included patients fulfilled age-adjusted NT-proBNP criteria (“rule-in” criteria) upon admission, according to established studies ,22. DiagPatient demographic, anthropometric, and clinical characteristics were recorded at admission.Ischemic cardiomyopathy was defined as the documented previous history of myocardial infarction . All patients underwent physical examination, 12-lead electrocardiogram (ECG), and chest X-ray imaging as per our standard institutional protocol for patients with dyspnea. Furthermore, all patients enrolled in the study received a standard TTE examination and advanced myocardial deformation analysis within 24 h of hospitalization, while imaging data was stored on the local workstation. Respective strain analyses were conducted “off-line” from the obtained images, when appropriate and as detailed in ® Cobas e601 NT-proBNP assay and electrochemiluminescence (ECLIA) method , high-sensitivity cardiac troponin I (hs-cTnI) was measured on the Abbott Architect ci16200 analyzer , while catestatin and soluble suppression of tumorigenicity (sST2) serum levels were determined by the enzyme-linked immunosorbent assay (ELISA) by using commercially available diagnostic kits . The C-reactive protein (CRP) was measured by immunoturbidimetry method on the Abbot Architect ci16200 platform. Other laboratory parameters were determined by using standard laboratory methods according to good laboratory practice. Fatty Liver Index was calculated by the online calculator by incorporating data obtained from body mass index , waist circumference (cm), GGT (IU/L), and triglycerides (mmol/L) [Furthermore, all patients had their peripheral blood sampled from the antecubital vein within 24 h of admission and the morning of the next day after fasting for laboratory analyses. All laboratory analyses were undertaken in the same certified in-hospital laboratory and handled by the same specialist in medical biochemistry that was an investigator in the present study. Liver function tests and cholestasis markers were obtained from all patients, and data were included on aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin, and albumin. A basic coagulation panel was ordered for every patient and consisted of prothrombin time (PT) normalized to the international normalized ratio (INR), activated partial thromboplastin time (APTT), and D-dimer assay. The N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were determined at the first contact by using Elecsys(mmol/L) .TM 9 ultrasound system , stored digitally, and analyzed off-line on the Echo PAC workstation installed on the PC . Data were acquired from parasternal long- and short-axis views and three standard apical views while for each view, cine loops were acquired by recording three consecutive cardiac cycles. All patients referred for echocardiography had a verified structural and/or functional myocardial alteration in conjunction with symptoms and fulfilled NT-proBNP criteria for HF. A single on-site investigator who was a cardiology consultant with expertise in cardiac ultrasonography and clinical experience in speckle tracking methods (Z.S.G.) performed all echo analyses including speckle-tracking deformation studies. A standard set of TTE measurements were taken while patients were at rest and in the left lateral decubitus position and all echocardiographic methods adhered to recommendations for cardiac chamber quantification by echocardiography in adults were endorsed by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) [A comprehensive TTE examination was performed in all patients on the same day when blood samples were collected. All images were acquired using Vivid (EACVI) . LVEF wa (EACVI) .Left ventricular global longitudinal strain (LV GLS) is an advanced echocardiographic index reflecting longitudinal shortening of LV during systole and can detect early subclinical myocardial dysfunction before LVEF is impaired . LV GLS max, m/s). TAPSE was acquired from the apical four-chamber (4-CH) view by placing an M-mode cursor through the tricuspid annulus and measuring the amount of longitudinal motion of the annulus at peak systole. For the measurement of RV FAC, RV end-diastolic area (RVED area) and RV end-systolic area (RVES area) were measured by manual planimetry, and RV FAC was calculated by the formula RV FAC = ((RVED area − RVES area)/RVED area) × 100. The RV S′ velocities were acquired by pulse-wave tissue Doppler in the apical 4-CH view and by placing sample volume (2–4 mm) in the middle of the basal segment of the RV free wall. Peak S′ velocities were measured in 5 consecutive cardiac cycles and the average value of these measurements was recorded. The TR Vmax was assessed by the continuous wave Doppler and was used to estimate RV systolic pressure (RVSP) in conjunction with right atrial (RA) pressure estimation based on the diameter and respiratory collapsibility of the inferior vena cava. RVSP was, therefore, calculated by using the simplified Bernoulli equation: RVSP = (4(V)2 + estimated RA pressure), where V represents TR Vmax (m/s). In some of the cases in which tricuspid regurgitant jets were not of sufficient quality, pulmonary artery pressure was estimated from the pulmonary flow acceleration time.RV function was examined according to the European Society of Echocardiography guidelines for the echocardiographic assessment of the right heart in adults . This exA two-dimensional speckle-tracking echocardiography of the RV free wall consisted of acquiring a 4-CH view with a focus on RV, with the frame rate ranging from 60 to 80 frames/s. A loop consisting of at least three cardiac cycles was recorded with good visualization of the RV lateral free wall to have at least one complete cardiac cycle  for the analysis without truncation. Gain settings were manually optimized for the best visualization of the RV free wall. ECG gating was ensured in all patients in order to obtain all images at nearly same heart rates. All images were acquired while patients were instructed to hold their breath in order to minimize possible breathing artifacts. RV endocardial border at the end-systolic frame was manually traced with the ROI being automatically generated by the software with further manual adjustment to include the RV wall thickness. Software analysis then automatically tracked the wall motion over a full cardiac cycle and ultrasonographer was allowed to manually readjust those segments of RV free wall that had suboptimal tracking quality. RV free wall was divided into three segments: basal, mid, and apex. The systolic longitudinal strain of the RV free wall (RV FWS) was calculated as the mean strain value recorded for basal, mid, and apical segments, while the strain of each segment was measured three times and averaged. Of note, RV FWS is expressed as a negative number where more negative numbers  reflect better RV systolic function, while less negative numbers (closer to zero) reflect worse RV systolic function.For the study purposes, the whole cohort in the present study was arbitrarily divided into two subgroups (21 vs. 21 patients) concerning the median RV FWS value that was found to be −16.5% (IQR 11.2%–20.1%) in our cohort. Accordingly, one group was designated as below median (RW FWS < 16.5%) therefore having a reduced RV FWS, while another group was designated as above median (RV FWS > 16.5%) thereby having better RV systolic function.®  and Prism 6 for Windows® . Data were presented as mean ± standard deviation (SD) or median (IQR-interquartile range) based on the variable distribution normality or as a number (n) with percentage (%). The normality of data distribution for continuous variables was assessed with the Kolmogorov–Smirnov and by visual estimation of Q–Q plots. For differences between groups, an independent samples t-test was employed for continuous variables with normal distribution, while the Mann–Whitney U test was used for continuous variables with non-normal distribution. Chi-squared (χ2) test was used to determine differences between groups with respect to categorical variables. Finally, the association of RV FWS with laboratory parameters of liver function and echocardiographic parameters of RV function were assessed through Pearson’s bivariate correlation analysis, and from this analysis, we reported correlation coefficients (r) and two-tailed statistical significance (p) values. To ascertain the association of RV FWS with laboratory parameters of liver function and to account for potential confounders, a multiple linear regression analysis was performed. Each variable of interest was tested in a separate regression model to reduce colinearity and potential overfitting effect, and each model was adjusted for following covariates, at all instances: age, sex, BMI, LVEF, NYHA functional class, eGFR, triglycerides, NLR, NT-proBNP levels, and estimated RVSP. From these analyses, we reported respective p-values and standardized β-coefficients with t-values. Results with the p-value < 0.05 were considered as statistically significant in all analyses.For all statistical analyses, we used SPSS Statistics for Windowsn = 23, 54.8%) had HFrEF phenotype followed by HFpEF  and HFmrEF . More than half of patients had nonischemic cardiomyopathy and the median age was 71.5 (62–76) years. There was an equal enrollment of men and women (21 vs. 21 patients) in the echo substudy, while mean LVEF and LV GLS values were 39.1 ± 16.0% and −10.1 ± 5.5%, respectively.All 42 patients had completed advanced echocardiographic examinations encompassing RV FWS and left ventricular global longitudinal strain (LV GLS) measurements, and this portion of the study was designated as CATSTAT-HF echo substudy. For the purpose of the analysis, patients were stratified into two groups according to RV FWS median that was −16.5% (IQR (−20.1)–(−11.2)%) in the present study, as measured. Patients in the subgroup below RV FWS median had mean RV FWS of −11.6% ± 2.8%, while those above RV FWS median had an average RV FWS of −21.3% ± 3.7%. Most of the patients were in NYHA III functional class, and the majority , 18 (42.9%) were former or current smokers, nearly two-thirds had dyslipidemia , more than a third of patients had type 2 diabetes mellitus , while 5 patients (11.9%) had concomitant chronic obstructive pulmonary disease. Furthermore, exactly half of the patients (n = 21) were obese (BMI ≥ 30 kg/m2), while almost half of the patients had atrial fibrillation . Patients below RV FWS median were significantly older (74 (IQR 68–77) vs. 65 (IQR 54–73) years, p = 0.040), had significantly higher circulating NT-proBNP levels (6266 (IQR 3089–12417) vs. 2315 (IQR 1171–5590) pg/mL, p = 0.038), significantly higher neutrophil-to-lymphocyte ratio , longer average length of stay , and reduced percentage of lymphocytes in peripheral blood  compared to patients above RV FWS median. No significant differences were observed between two groups with respect to systolic function, LVEF and LV GLS, while they also did not significantly differ in respect to other baseline parameters , a Pearson’s bivariate correlation analysis showed that RV FWS significantly correlated with total bilirubin , ALP , albumin , prothrombin time-INR , and the thrombocyte count  independently predicted RV FWS that was set as the dependent outcome variable. When these laboratory variables were adjusted for relevant confounders in the separate models of multiple linear regression, as described in max. A subgroup of patients with RV FWS below median had significantly reduced TAPSE , RV FAC , and RV S′ velocity  compared to patients with RV FWS above median, while no difference was observed between the two groups in respect to TR Vmax . The estimated RV systolic pressures (RVSP) did not significantly differ between the groups .The mean values of RV function echo parameters in the whole cohort of patients were 16.3 ± 5.2 mm for TAPSE, 32.5 ± 9.5% for RV FAC, 10.0 ± 3.0 cm/s for R S′ velocity, and 2.9 ± 0.7 m/s for the TR Vmax . Furthermore, RV FWS was independently associated with levels of total bilirubin and ALP reflecting a primarily cholestatic pattern of liver injury, while no significant association was observed with respect to AST and ALT as markers of hepatocellular injury. Similarly, no significant association was established between RV FWS and GGT. Importantly, a significant and independent association was established between RV FWS and markers of synthetic liver function such as albumin and PT-INR as well as thrombocyte count. Of conventional RV function echocardiography indices, RV FWS was significantly associated with TAPSE, RV FAC, and RV S′, while no significant association was established with TR VThese are novel results in the context of RV mechanics and biochemical parameters of liver function since, to date, RV free wall strain as the specific marker of RV systolic function was not previously examined in the context of cardiohepatic interactions, particularly in the setting of HF. These results are more firmly established given the fact that no significant differences were found between compared groups in a vast majority of baseline parameters except for age, hospital length of stay, lymphocyte indices, and circulating NT-proBNP levels. Importantly, both groups were similar in respect to their baseline LV systolic function, LV global longitudinal strain, NYHA functional class, Fatty Liver Index (FLI), and renal function. A potential confounding effect of unrecognized PAH was also minimized since both groups had similar estimated pulmonary artery pressures and tricuspid regurgitation jet velocities. Even more, no significant differences were observed in pharmacotherapy use and circulating levels of CRP and relevant cardiac biomarkers reflecting cardiomyocyte injury, adverse ventricular remodeling, and sympathetic nervous system activity such as hs-cTnI, sST2, and catestatin. Finally, multiple linear regression analysis adjusted for relevant confounders validated these observations as RV FWS was independently associated with total bilirubin, ALP, albumin, thrombocyte count, and prolonged PT-INR but not to AST, ALT, and GGT.milieu, when chronically present, promotes atrophy of hepatocytes and causes perisinusoidal edema, thus significantly affecting diffusion of oxygen and nutrients to the hepatocytes [Due to the inability to maintain adequate systemic perfusion of tissues and organ systems, HF must be perceived as a disease of all organs and all cells in the body. Arterial hypoperfusion dominates in the acute form of HF and leads to hypoxic hepatitis through a postulated mechanism of ischemic-reperfusion injury, while passive congestion is the major contributor in congestive hepatopathy secondary to chronic HF ,30. Thisatocytes . Similaratocytes . These catocytes , and ourIn terms of laboratory derangements in cardiohepatic syndrome, it is recognized that passive liver congestion causes manifest elevations of hepatic and cholestatic enzymes, and this is linked to impaired hemodynamic status ,37. MoreRV dysfunction is highly prevalent and is an important harbinger of poor prognosis among patients with established left-sided HF, both in HFrEF and HFpEF clinical phenotypes ,43. In tTaken together, RV FWS should be regarded as a reliable indicator of RV function among HFrEF patients, however, more evidence is required to establish its role in HFpEF patients. Finally, an important finding in our study is that RV FWS did not significantly correlate with RVSP and tricuspid regurgitation, while it did correlate with echocardiographic indices reflecting RV function of which strongest correlation was established with RV S′. Furthermore, both compared groups had similar LV systolic function and LV GLS. These findings suggest that we indeed can attribute observed results to isolated RV dysfunction, independently of potential confounding by concomitant LV dysfunction, elevated pulmonary pressures, and/or the degree of tricuspid regurgitation. Finally, all multiple linear regression models were also adjusted for baseline NYHA class reflecting functional syndrome severity, NT-proBNP levels, and NLR to account for these variables as potential confounders.There are some limitations to this study. This was a single-center cross-sectional study. Therefore, no causal inferences can be made, and there is an inherent possibility of nonmeasured confounders. Furthermore, it could not be fully excluded that some of the subjects had relevant pulmonary hypertension that could affect RV function since no assessment with invasive right heart catheterization was performed. However, noninvasive assessment of pulmonary hypertension in patients with cardiac diseases with Doppler echocardiography provides good sensitivity (87%) and specificity (79%) and has a high degree of correlation (r = 0.87) with right heart catheterization . ImportaThe results of this study, for the first time in the literature, show that reduced free wall strain of the RV is independently associated with adverse perturbations of biochemical parameters of liver function, particularly those reflecting cholestasis, among patients with acute worsening of HF. This relationship seems independent of baseline left ventricular systolic function, NYHA functional class, degree of tricuspid regurgitation, estimated pulmonary artery pressure, and natriuretic peptide levels. Furthermore, RV FWS was a good correlate of RV function concerning more conventional RV functional indices in the AWHF population. These findings might be of clinical value since reduced RV FWS, as an indicator of RV longitudinal systolic function, might indicate the presence of congestive hepatopathy among HF patients and vice versa—patients with a marked cholestatic pattern of liver injury per laboratory findings should be investigated for the possible RV dysfunction.


Rapid and accurate diagnosis is crucial for survival in medical emergencies.Unpredictability, breadth of content and the frequent need for speed are the challenges, which characterize emergency medicine. Emergency medicine has, therefore, always found itself in something of an interdisciplinary void; an area in which a broad basis of medical knowledge, complementary structures of traumatology and methods of anesthesiology and intensive medicine are required to act in symphony. Declared a special science at the “International Congress for Rescue Services” in 1908 [The combination of broad expertise and specific skills is the only way in which the entire rescue-chain, from the site of the event to the final stabilization of acutely ill patients, can be completed. A quick and accurate diagnosis is essential before any acute treatment. The broad canon of diagnostic measures has evolved from general “basics” to rapidly emerging “high-end” diagnostics.A complete discussion of diagnostics in emergency medicine is clearly not feasible within the scope of this essay. However, this article intends to provide an overview of emergency diagnostics. The diagnostic methods addressed herein should be part of the basic diagnostic armamentarium of all clinicians and can be largely applied not only to patients at an emergency department but likewise to patients at a general ward.3:40 a.m.; telephones ringing; flashing lights; devices illuminating; tense silence; fast hands; ringing monitor alarms; a pale patient; bathed in sweat; barely awake. Emergency! Time is running out!The ABCDE approach is highly recommended in clinical emergencies for initial assessment, reassessment and treatment. The aim of the ABCDE assessment is to identify most life-threatening problems firstOne of the most prominent systematic approaches for the assessment of seriously ill or injured patients is the ABCDE approach . It can be used from the preclinical assessment on scene, through the arrival at the emergency room, to the re-evaluation on hospital wards or intensive care units. After the first overall impression , systematic assessment is performed following the mnemonic acronym “ABCDE”. Potentially life-threatening respiratory problems are considered first, followed by other respiratory issues in the second instance and thereafter hemodynamic problems, etc. . Particular attention should be paid to the threatening four B’s, “Brust – Bauch – Becken – Beine” (chest – abdomen – pelvis – legs) [ – legs) .Reason for AlarmA 67-year-old woman complains of acute shortness of breath and palpitations; yesterday she was discharged from a neurological ward after successful treatment of intracerebral haemorrhage.Past medical historyICHArterial HypertensionAECHEThyroidectomyMultiple joint prostheses Current MedicationEnoxaparin: 20 mg s.c., 1‑0-0‑0Gabapentin:300 mg tablets, 1‑1-1‑0Pantoprazole: 40 mg tablets, 1‑0-0‑0Lisinopril: 20 mg tablets, ½‑0-0-½Amlodipine: 5 mg tablets, 0‑0-0‑1Zolpidem: 10 mg tablets, 0‑0-0‑1Fentanyl: 25 mcg TTS, Change every 3 daysAllergies: Cotrimoxazole, AspirinAlcohol/nicotine/drug use: negatedTaking patients’ history and physical state remains essential in any emergency diagnostic procedure, despite new methodsIn addition to the immediate recognition of life-threatening conditions using standardized schemes (see above), emergency medicine requires rapid identification of the causal background by inspection, palpation, percussion and auscultation. In many cases, this is the only way to start adequate therapy. Impaired consciousness in emergency patients usually leads to serious loss of vital information. In such situations, implicit evidence is important.General stateReduced, Height: 160 cm, Weight: 62 kgVital signs and Glasgow coma scaleVital signs: HR 105/min, BP 70 mmHg syst., RR 30/min, SpO2 98% at 15l/min O2 insufflation, Temperature 36.5 °C, GCS 15Cardiovascular/vascular statusCor: rhythmic, tachycardic, 3/6 systolic murmur p.m. 2 ICR leftThorax/LungsTachypnea, RR 30/minAbdomenLiver and spleen not palpable, peristaltic sounds over all 4 quadrants, no resistances, no tenderness on palpationExtremities/spineAll peripheral pulses palpable, varices on both sides, no edema, spine: no pain on percussionCorrect assessment of a patient’s condition in an emergency setting requires a high level of focus on specific symptoms. In the differential diagnosis of abdominal pain, for example, inspection of the abdomen for the presence of Cullen’s sign  and Grey Turner’s sign (bruising of the flanks) or evaluation of the hands for palmar erythema or white nails can point to either pancreas- or liver-associated disease. The palpation of Lanz’s, McBurney’s and Murphy’s spot helps to distinguish appendicitis from cholecystitis. The evaluation of Meyer’s , Homan’s  or Payer’s  signs may not only indicate deep vein thrombosis, but potentially also an associated pulmonary embolism. In a similar manner, Kussmaul’s sign  may suggest pericardial effusion, Kussmaul’s breathing suggests metabolic acidosis and a typical “flapping” during pronators drift test may indicate hypercapnia. The extraordinary range of potentially relevant findings and their interpretation require training and expertise .Scoring systems represent an important instrument for diagnostics and stratification in emergency medicine. Particularly important during the initial assessment of a patient, scoring systems are found throughout the entire spectrum of emergency medicine.Diagnosis facilitating scoring systems are found throughout the entire spectrum of emergency medicineThe principle behind “scoring” is to systematically record certain characteristics and then to weight and sum them, thus forming an overall assessment. Scoring is supposed to facilitate the estimation of the probability of a disease in general , YEARS algorithm; sepsis—qSOFA score), the severity of a clinical condition (e.g. NACA score) or the associated urgency of a certain intervention  [e score) .Blood gas analysis is an integral part of the assessment of critically ill patients and provides information on the etiology and severity of various disease processes.Blood gas analysis has already become an indispensable standard tool for the assessment of respiratory, circulatory and metabolic disordersSince Barcroft and Henderson developed the necessary experimental and mathematical methods almost 120 years ago, blood gas analysis has become a standard tool for the assessment of respiratory, circulatory and metabolic disorders  at the emergency department has been proposed to reduce time-delay to treatment, increase timely discharge rates and improve patient outcomes  Dipstick , which allows for rapid and accurate detection of thrombin and factor Xa inhibitors in human urine [an urine . QualitaCritical conditions like trauma and bleeding or the need for urgent surgery (as in thoracic aortic dissection for example) commonly demand immediate assessment of the presence of effective anticoagulation. The unreliability of global coagulation studies in detecting DOAC anticoagulation, however, severely complicates the care of these patients and stresses the need for novel time-effective diagnostic tests. A urine based POC DOAC test may become a useful bedside method to rapidly and accurately assess DOAC anticoagulation in clinical practice at Emergency Departments.The electrocardiogram is of great importance in emergency medicine Fig. , not onlSgarbossa’s/Smith’s criteria facilitate diagnosis of myocardial infarction in presence of left bundle branch block or paced rhythmSgarbossa’s/Smith’s criteria  in at least one lead (5 points)B.Concordant ST-segment depressions of at least 1 mm in V1 to V3 (3 points), orC.Excessive discordance with ST-segment elevation defined as greater than 4 mm and negative QRS complex (2 points)Based on data from the GUSTO‑1 trial, Sgarbossa et al. developed an electrocardiographic prediction rule for the diagnosis of MI in patients with chest pain and left-bundle branch block:A score of ≥3 points has a high specificity (98%), but low sensitivity for the presence of myocardial infarction , 16. TheThe differential diagnosis of arrhythmias can be improved by Lewis leadsLewis leads: The differential diagnosis of arrhythmias may require the use of special ECG leads. When atrial flutter is suspected, for example, flutter waves may be more easily detected in lead I using the Lewis leads, which help to visualize atrial activity. Lead placement is shown in Fig. Sonography is a particularly important diagnostic tool in modern emergency medicine. New portable ultrasound devices enable emergency physicians to perform advanced diagnostics at the scene Fig. .The FAST (Focused Assessment with Sonography for Trauma) concept is a well evaluated sonographic diagnostic toolThe widely used and best evaluated FAST concept (Focused Assessment with Sonography for Trauma), for example, serves as a structured examination procedure [rocedure . Originarocedure , 24. In rocedure . Delays rocedure . The extThe use of the FAST concept also retains its significance in the context of intramural emergency medicine. It serves not only as a decision-making aid in time-critical situations , but canThe measurement of the diameter and the breath dependent variation in diameter of the inferior vena cava (IVC) allows for non-invasive estimation of the central-venous or dextro-atrial pressure. The IVC is visualized through a subcostal view; maximum and minimum diameters are measured distal to the hepatic vein and right atrium to estimate the percentile caliber variation. The deducible estimation of volume status is considered to be well proven in both spontaneously breathing and mechanically ventilated patients –29. A diA diameter of the inferior vena cava <10 mm suggests a positive hemodynamic response to fluid administrationExcursion of the endocardium to the centerSystolic thickening of the myocardiumExcursion of the anterior leaf of the mitral valve (MK) to the septumThe assessment of left ventricular (LV) systolic function and ejection fraction (LVEF) is one of the most common echocardiographic examinations in emergency rooms. It enables rapid distinction between normal and reduced LVEF and facilitates the discrimination between cardiac and pulmonary pathologies. Qualitative and semi-quantitative methods such as visual estimation to assess systolic LV function are particularly appropriate for use in emergency medicine and are suited to it due to their good correlation with volumetric methods. The visual assessment of the systolic LV function is based on three elements:ExcursionThe latter semi-quantitative parameter is measured as the lowest distance between the anterior leaf of the mitral valve and the interventricular septum in M mode. It shows a 100% sensitivity for the identification of patients with LVEF <30% at a cut-off of >7 mm . More soRapid detection of acute RV dysfunction can significantly affect patient management and is an independent predictor of mortality in pulmonary embolism, ARDS and acute myocardial infarction –39. EyebEchocardiographic criteria of RV dysfunction include: RV dilatation  or an elevated right/left ventricular end-diastolic diameter ratio (cut-off of 0.9 or 1.0), an abnormal motion of the interventricular septum, an elevated tricuspid valve regurgitation velocity (cut-off 2.7 or 2.8 m/s) and hypokinesis of the RV free wall . A D-shaRight ventricle dilation and right ventricular dysfunction on emergency physician performed TTE were shown to be highly specific (but not sensitive) for the presence of pulmonary embolism [. Measurement of peak tricuspid regurgitant velocity  helps to assess the probability of pulmonary hypertension Right venMcConnell’s sign is characterized by RV free wall hypokinesis with apical sparing (preserved function of the right ventricular apex). It is considered to be highly specific for the acuity of pulmonary embolism but lacks sensitivity , 45.McConnell’s sign is considered an early and highly specific indicator of acute massive pulmonary embolismAmong the quantitative methods for assessing RV function measurement of the TAPSE is frequently used in emergency medicine. The maximum longitudinal excursion of the lateral tricuspidal annulus is measured in M‑mode in an apical 4‑chamber view between the end of the systole and the end of the diastole. A TAPSE >16 mm correlates well with normal RV function; abnormal TAPSE suggests poor clinical outcome in several pathologies, such as ARDS, pulmonary embolism and sepsis [d sepsis .The question of a possible pericardial effusion can be answered both accurately and reliably using echocardiography . NormallThe key characteristic of pericardial tamponade is an impaired diastolic filling of the right ventricle, which leads to a decrease in the LV stroke volume. Due to the low venous flow, the breath-dependent caliber variation of the IVC is reduced. Dilatation of the IVC (>2 cm) and hepatic veins is a sensitive sign (92%) of pericardial tamponade . ConversEvidence of a transition point between normal and absent pleural gliding (lung point) has a 100% specificity for the presence of pneumothoraxIn the differential diagnosis of “shortness of breath”, pulmonary ultrasound (LUS) has high diagnostic accuracy  in detecting pulmonary edema, pleural effusion and pneumothorax [mothorax –50. The The first step is to visualize the pleura and pleural gliding, a horizontal movement of the pleural line with respiration. Absence of pleural gliding may indicate pneumothorax, but may also be seen in pleural adhesion and should thus be assessed in conjunction with other echo features suggestive of pneumothorax. Evidence of a transition point between normal and absent pleural gliding (lung point) has a100% specificity for the presence of pneumothorax . In M moLung parenchyma can be assessed using a low frequency transducer , 52. A‑lTEE is considered both safe and clinically indispensable in emergency medicine . The fouSonographic assessment in case of insufficient transthoracic imaging conditions Detection of left atrial appendage thrombus in patients with atrial fibrillation of unknown onset prior to undergoing cardioversionEvaluation for infective endocarditis (IE) in patients with high clinical suspicion of IE and a negative or non-diagnostic TTE, and in those with intracardiac device leads or suspected prosthetic valve IE.Investigation of ventilated patients Applications include:TEE is furthermore indispensable for the visualization and confirmation of the position of ECMO guidewires and cannula while treating patients with refractory cardiac arrest using peripheral bifemoral VA ECMO . The midUltrasound-based examinations are generally regarded as the most important non-invasive vascular imaging, with both B‑mode and color Doppler providing highly reliable information . In deepThromboelastometry is a diagnostic procedure used to assess hemostasis, and is based on the viscoelastic properties of whole blood. It has already been used for more than 20 years in cardiac and transplant surgery, and is now increasingly performed during the acute care of medical patients with bleeding or thrombotic disorders. It is used for both the detection of abnormal coagulation states and acute therapeutic management thereof –71. The Laboratory-based assays tend to be time-consuming. Additionally, conventional coagulation tests are not always suitable for supporting the indication of treatment with blood components, or the checking thereof –74. ResuThromboelastometry is a diagnostic procedure used to assess hemostasis, and is based on the viscoelastic properties of whole bloodIn TEG, a pen is immersed in an oscillating beaker containing the blood sample. In ROTEM the beaker is stationary, whilst the pen oscillates. Detection is performed using optical methods. When clots form, the gap between the beaker and the pin is bridged and the oscillation from the beaker is transferred to the pin in the case of TEG; with ROTEM the rotation of the pin is reduced. The movements are recorded in each case and the behavior is plotted in the characteristic curve form  is used to assess the traditionally intrinsic pathway, tissue factor activation (EXTEM) is used to assess the extrinsic pathway of coagulation. While the addition of heparinase (HEPTEM) or cytochalasin D (FIBTEM) helps to identify heparin effects, fibrinogen deficiency or fibrin polymerization disorders, inhibition of fibrinolytic agents by adding aprotinin (APTEM) to the blood sample may reveal the presence of hyperfibrinolysis in a timely manner .Despite viscoelastic POC coagulation tests, several platelet function testing devices for the rapid assessment of the effects of antiplatelet medications are available  100, the Multiplate analyzer, the Verify-Now test, ROTEM platelet). Presentation of these and other POC coagulation methods however are beyond of the scope of this article.From correct sampling to transport, preparation and/or manual analysis, to the final interpretation of findings, laboratory analysis of blood samples requires a complementary interdisciplinary interplay, especially under time pressureLaboratory analysis of blood samples is of extraordinary importance in emergency medicine. From correct sampling to transport, preparation and/or manual analysis, to the final interpretation of findings, it requires a complementary interdisciplinary interplay, especially under time pressure. Careful interpretation of laboratory results by emergency physicians is crucial [ crucial , 77, 78 These laboratory findings may be suggestive of acute myocardial damage, hemodynamic alterations and increased clotting activity  may be helpful if the result of a CT scan is inconclusive. Due to its high sensitivity in ischemia (in particular brainstem ischemia) and encephalitis it can provide important information in the case of normal CT findings –90. If tAcute MRI may be helpful if the result of a CT scan is inconclusiveCT shows bilateral pulmonary embolism indicated by an absence of contrast media in the left main pulmonary trunk. Contrast reflux into the hepatic veins via the IVC are a controversial sign of right heart strain. Pulmonary infarction, atelectasis or pleural effusion were not present (Fig. ent Fig. .Fig. 8CaNovel diagnostic tools at the Emergency Department increase the precision and speed of emergency diagnosticsNovel modern laboratory, POC and imaging diagnostic tools at the Emergency Department increase the precision and speed of the emergency diagnostic work-up process from the initial symptom to the final diagnosis. Hand in hand with better modern treatment approaches, diagnostics in emergency medicine are continuously improving.https://www.intensivmedizin.at/ – Österreichische Gesellschaft für Internistische und Allgemeine Intensivmedizin und Notfallmedizinhttps://www.aaem.at/termine.html – Österreichische Vereinigung für Notfallmedizinhttp://www.notarzt.at/ – Östrreichische Gesellschaft für Notfall- und Katastrophenmedizin