T1 mapping versus assessment at a single ventricular level.Our objectives involved identifying whether repeated averaging in basal and mid left ventricular myocardial levels improves precision and correlation with collagen volume fraction for 11 heartbeat MOLLI T1 mapping precision, a cohort of 15 healthy volunteers underwent two CMR scans on separate days using an 11 heartbeat MOLLI with a 5(3)3 beat scheme to measure native T1 and a 4(1)3(1)2 beat post-contrast scheme to measure post-contrast T1, allowing calculation of partition coefficient and ECV. To assess correlation of T1 mapping with collagen volume fraction, a separate cohort of ten aortic stenosis patients scheduled to undergo surgery underwent one CMR scan with this 11 heartbeat MOLLI scheme, followed by intraoperative tru-cut myocardial biopsy. Six models of myocardial diffuse fibrosis assessment were established with incremental inclusion of imaging by averaging of the basal and mid-myocardial left ventricular levels, and each model was assessed for precision and correlation with collagen volume fraction.For assessment of T1 maps provided improved precision (Intraclass correlation 0.93 vs 0.84) and correlation with histology (R2 = 0.83 vs 0.36) for diffuse fibrosis compared to a single mid-ventricular level alone. ECV was more precise and correlated better than native T1 mapping.A model using 11 heart beat MOLLI imaging of two basal and two mid ventricular level averaged T1 mapping sequences with repeated averaging could be considered for applications of 11 heartbeat MOLLI, especially when small changes in native T1/ECV might affect clinical management. T1, of the myocardium is regarded as a useful imaging biomarker, as it can change with cardiac pathology and is known to be associated with functional capacity and mortality [T1 following administration of a gadolinium–based contrast agent (Gd): namely, shortening of T1, which manifests as bright signal intensity on conventional inversion-recovery gradient echo sequences. This has been used as the primary tool for identification of focal (or replacement) fibrosis, indicative of scar, and has entered clinical routine for multiple pathologies, including myocardial infarction and viability [The longitudinal relaxation time, ortality . Traditiiability , cardiomiability , 7, congiability  and valviability , 9.T1-weighted inversion recovery sequences is that they rely on the nulling of signal in normal myocardium to highlight concentrations of Gd in fibrotic areas. In cases of diffuse  fibrosis, however, where the myocardium can be globally affected, the myocardial signal may appear isointense and, hence, lack sensitivity in identifying fibrosis [T1 mapping CMR sequences have been developed, based on the Modified Look-Locker inversion recovery (MOLLI) sequence first described by Messroghli and colleagues [A limitation of fibrosis . To addrlleagues . These alleagues –16.T1 mapping sequence acquire a total of 8 or 9 T1-weighted images over 11 heart beats [T1-weighted images in a 3b(3b)3b(3b)5b scheme [T1-weighted MOLLI source images from 11 to 8/9 may reduce T1 precision, it also has the distinct advantage of increased reliability through better patient breath-holding. Therefore, the newer, faster sequences have enabled extended applications in patients with poorer breath-holding ability. However, before a new sequence is fit for clinical application, assessment of precision and accuracy is required, benchmarked against the reference standard of histologically derived quantification of diffuse fibrosis.Recent iterations of the MOLLI rt beats , 17, in b scheme . While rexplore the effect of six imaging models 3b and 4b(1b)3b(1b)2b 11 heart beat MOLLI prototype in patients who have left ventricular myocardial biopsy at the time of aortic valve surgery; andT1 mapping, partition coefficient, and extracellular volume fraction (ECV).explore the relative precision and correlation with CVF of native We examined an 11 heartbeat (11HB) MOLLI prototype, by Siemens, with native 5b(3b)3b and post-contrast 4b(1b)3b(1b)2b, which is referred to in the main text as MOLLI for brevity. This sequence has undergone little exploratory validation, and thus the aim of this work is to:T1 mapping precision, and a group of aortic stenosis patients for estimating T1 mapping correlation with CVF. Written consent was obtained from all patients and volunteers, and the study was conducted after local research ethics approval from the Royal Brompton and Harefield NHS Foundation trust and in accordance with the Declaration of Helsinki principles for Medical Research.Two cohorts of participants were recruited for this work: a group of healthy volunteers for estimating Healthy volunteers taking no medication and with no known medical conditions were recruited following advertisements on public notice boards. The volunteers underwent a detailed health questionnaire and blood screening to measure haemoglobin, renal function, liver function, thyroid function, and C-reactive protein. The bloods were measured in a clinical biochemistry laboratory. Additionally, blood pressure, heart rate, and temperature were recorded. All volunteers underwent electrocardiography. In the event that an abnormality  was detected that could have affected the results, the participant was excluded.A cohort of patients with severe aortic stenosis, scheduled for surgical aortic valve replacement, was recruited from outpatient clinics or inpatient wards at the Royal Brompton Hospital, London, UK. The patients were excluded if they had any contraindications to CMR or if they were scheduled for surgery for more than one valve. Patients who were scheduled for concurrent aortic valve replacement and coronary artery by-pass grafting (CABG) were included. As this was a correlation study, the patients were not excluded if they had treated hypertension, hyperlipidaemia, or diabetes.R2 correlation of at least 0.8 with 80% power. We opted to double this number to ten patients, giving us 90% power to detect a statistically significant correlation assuming that the true R2 correlation was at least 0.6.Assuming similar correlations to histological CVF to previous published data , we estiAll CMR imaging was performed on a 1.5 T scanner . The quadrature body coil was used for radiofrequency transmission with 12–18 elements of an anterior and posterior cardiac parallel array coil for reception. The standard manufacturer wireless-ECG was used as in routine clinical work.T1 mapping acquisition protocol was the same for both volunteers and aortic stenosis patients. Following adjustment of the scanner reference frequency to the predominant Larmor nuclear magnetic resonance precession frequency of the signal received from a cuboid volume region over the left-heart , MOLLI T1 mapping was applied with the following parameters: Single-shot balanced steady-state free-precession images, field-of-view = 360 × 306 mm, slice thickness = 8 mm, alpha pulse flip angle = 35o, 7/8ths partial ky acquisition with 1/8th zero-filling, a generalised autocalibrating partially parallel acquisition acceleration factor of 2 with 24 central ky lines fully acquired to obtain receiver coil profiles, and 1085 Hz/pixel ADC sampling bandwidth. The T1 weighting was initially TI = 120 ms, incrementing by 80 ms at the start of each Look-Locker set. Two different MOLLI acquisitions were used depending on participant heart rates: a high-resolution acquisition for heart rates less than 90 bpm and a low-resolution acquisition for heart rates greater than 90 bpm. Two different sequences were required because the high-resolution acquisitions were too long to fit into the stationary diastole phase for faster heart rates. The following parameters varied between high-resolution and low-resolution setups, and these differences have been shown to have negligible impact on T1 values while maximising image quality [The High resolution: TR/TE = 2.6/1.12 ms, 84 acquired PE lines, single-shot image duration 220 ms, Acquired pixel size 1.4 mm (FE) × 2.1 mm (PE).Low resolution: TR/TE = 2.4/1.0 ms, 76 acquired PE lines, single-shot image duration 182 ms, Acquired pixel size 1.9 mm (FE) × 2.4 mm (PE).T1 values and a 4b(1b)3b(1b)2b scheme was used for post-contrast T1.Further, for the low- and high-resolution MOLLI acquisitions, two different MOLLI sampling schemes were used pre- and post-contrast : a 5b. Then, starting fifteen minutes after Gd administration, post-Gd MOLLI T1 maps were acquired at basal and mid-ventricular levels  using the 4b(1b)3b(1b)2b scheme, again with low or high resolution depending on the heart rate. In total, four native T1 maps and four post-contrast T1 maps were obtained. The addition of a complete T1 mapping protocol to a clinical scan increased the total scan time by about 5–7 min per patient.A total of four native To assess interscan reproducibility, the healthy volunteers underwent a second CMR scan within 60 days of the first. To mimic routine clinical practice, the staff undertaking the second scan were unaware of the exact slice position used for acquisition in the first scan. The aortic stenosis patients underwent a single CMR scan as close to the day of surgery as possible.T1 values, dedicated software CMR Tools  were drawn on the T1myopost and T1myopre are the T1 values of post-contrast and native myocardium, and T1bloodpost and T1bloodpre are the T1 values of post-contrast and native blood, respectively.Once native and post-Gd myocardial and blood values and haematocrit were obtained, extracellular volumes (ECVs) were calculated as shown in Eq. :1\docume2. Endocardium, subendocardial fibrosis and subendocardial fat, procedure-related optically empty spaces and epicardial fat were eliminated from analysis. Subsequent image analysis was performed to determine the level of fibrosis including reactive, band-like perimysial collagen depositions and perivascular fibrosis, defined as collagen surrounding arterioles. Fibrosis was calculated as the collagen volume fraction (%) per square millimeter, as previously described [All aortic stenosis patients included underwent successful myocardial biopsy intraoperatively using the following standardised protocol: Once the chest was opened and cardiopulmonary bypass was established, a long near-transmural left ventricular “tru-cut” biopsy was taken. The aim was to undertake multiple biopsies provided that patient safety was not compromised. Upon completion of the biopsy, the myocardium was sutured, if required, and surgery continued as normal. The myocardial biopsies were immediately fixed in warm buffered 4% formalin. Histological analysis of fibrosis was undertaken on 3-µm-thick sections from formalin-fixed, paraffin-embedded endomyocardial biopsies using a special collagen stain (Picrosirius red). Quantification was performed using standardised semiautomatic image analysis software  on images of 14 randomly chosen consecutive high-power fields (×200 magnification), which were obtained with a Nikon Eclipse E400 light projection microscope . The 14 high power fields equaled 1 mmescribed .T1 values, partition coefficients, and ECVs were compared to the histologically identified collagen volume fraction (CVF). Intraclass correlation coefficients (ICC) were calculated using ‘R’  and used to assess agreement in the healthy volunteer ‘precision’ cohort. For the aortic stenosis ‘correlation with CVF' cohort, graph-plotting and analysis was again undertaken using the statistics package ‘R’. The six models, A–F, described for CMR estimation of myocardial diffuse fibrosis were compared to identify the most reproducible model (from the volunteer precision cohort) and most accurate/correlating with CVF (from the aortic stenosis biopsy cohort). There is no published method of incorporating both precision and accuracy (via correlation with CVF) in one single measurement for such imaging work. We therefore proposed and calculated the product of the scan-rescan R2 values for the volunteer (precision) and ECV-histological fibrosis R2 for aortic stenosis biopsy patients (correlation with CVF) as a single combined measure of correlation with CVF and precision for this imaging modality, described in this manuscript as Product of R2.The CMR native T1 maps, post Gd T1 maps, partition coefficient and ECV results are shown in Table T1 mapping images were obtained. No volunteer was excluded due to respiratory drift, cardiac motion artefact, or inappropriate cardiac triggering. There was no statistically significant difference between the two scans with regards to heart rate, blood pressure, or haematocrit . Both interstudy T1 and interstudy ECV differences showed excellent results , 0.996 for partition coefficient (p < 0.001) and 0.999 for ECV (p < 0.001). Interobserver ICCs were: 0.993 for native T1 (p < 0.001), 0.985 for partition coefficient (p < 0.001), and 0.997 for ECV (p < 0.001).Both intra- and interobserver variability were excellent. Intraobserver ICCs were: 0.995 for native T1 mapping images were free from disqualifying artefacts and were diagnostic in all participants. In one patient the initial native T1 maps needed repeating in view of poor breathholding. This was appreciated during the scan, and therefore was repeated before proceeding to Gd administration. The repeat maps were of acceptable quality with no apparent respiratory drift, cardiac motion artefact, or inappropriate cardiac triggering. All patients had apical–lateral wall biopsies taken intraoperatively and no patients had biopsies from all three basal, mid, and apical levels due to surgical concerns. One patient had to be taken back to theatre within 24 h from surgery for bleeding, which may have been related to the apical myocardial biopsy sampling. The patient made a good recovery and discharged home within five days with no further sequela. No other side-effects relating to the myocardial biopsies were seen. Therefore, the basal and/or mid-myocardial T1 values were taken as a surrogate for a global T1 value and were correlated with histology from the apical–lateral wall. Microscopic views of the sections prepared from the biopsies are shown in Fig. Ten consecutive patients with symptomatic severe aortic stenosis scheduled for surgical valve replacement underwent CMR and intraoperative myocardial biopsies: eight male, mean age = 71 ± 10 years, and three with significant major epicardial coronary artery disease (defined as disease >50% of lumen diameter) requiring CABG at the time of the operation. Of these patients, five received treatment for hypertension and their blood pressure was well controlled at the time of the CMR (BP < 140/90 mmHg), four had treated hyperlipidaemia, two had chronic obstructive pulmonary disease requiring bronchodilators and two had prior distant history of neoplasia (breast/bladder). Of the three patients requiring CABG, one had 2-vessel CABG (left anterior descending (LAD) and circumflex) and the other two had single vessel CABG (one of the LAD and one of the intermediate coronary artery respectively). No patients suffered from diabetes. All patients tolerated the CMR well and the T1 maps, partition coefficient, and ECV were assessed using histology. The histologically derived CVF was plotted against each of these parameters, as shown in Table T1 values from model F (which had shown best correlation) showed a moderate, statistically-significant correlation with the histologically obtained fibrosis burden, with R2 = 0.42, and p = 0.046. However, the partition coefficient and ECV both showed strong correlations with histology, with R2 = 0.81 and R2 = 0.83, and these both were statistically significant, with p < 0.001 , the correlation with histology was only modest, and was not significant , similar to data from published studies that used only one mid-level T1-map [T1 maps, and including the basal level as well as the mid-ventricular-level in this averaging improved the correlation significantly: R2 = 0.72, p = 0.002 when the average of a single basal and single mid-level image was used for ECV (Model E) and importantly R2 = 0.83, p < 0.001 when acquisition was repeated at both basal and mid-levels (Model F) as shown in Table Having established that ECV was the most accurate imaging parameter from  T1-map , 20. IncT1 mapping. We therefore devised a new model, incorporating the product of the R2 from the precision cohort and R2 from the ‘correlation with CVF' cohort as a unique parameter for each model. The results are shown in Table T1 maps to calculate ECV, was the most precise method with the best correlation with CVF.To allow us to clarify the relative incremental addition of imaging for each model combining both accuracy (via correlation with CVF) and precision we sought a single parameter for each model to incorporate both correlation with CVF and precision. However, such a single measure has not been described for T1 mapping sequence. Furthermore, this is the first time a study has reported a model of incremental image acquisition and averaging of basal and mid-ventricular T1-measurements as a means of obtaining an average of the global T1-mapping ECV. The volunteer cohort demonstrated that four models of slice acquisition and averaging showed an excellent interscan correlation. Model A native T1 mapping (one native T1 mid-ventricular level slice), Model E native T1 mapping , Model C ECV (average of ECV of two mid-level slices), and Model F ECV  all showed excellent interscan reproducibility, with R2 ≥ 0.90.Any new CMR sequence needs to show both good accuracy and precision to become clinically relevant. In this work, we used two cohorts to establish precision and correlation with CVF (as a surrogate for accuracy) for an as yet non-validated R2 = 0.36, p = 0.068. A model utilising the basal level alone (Model B) showed good correlation with histology , while a model based on one basal level being imaged twice and averaged (Model D) showed better correlation . The best correlation was achieved by a model having one basal and one mid-ventricular slice being imaged twice each and averaged . Incorporating both precision and correlation with CVF parameters into the Product R2, showed that ECV calculated from Model F was the most accurate and precise. We speculate that the improved correlation and precision associated with Model F may relate to the incorporation of further areas of the myocardium  and the repeat scan may serve to average out any potential errors associated with imaging a single slice.The correlation with CVF was assessed using a cohort of ten patients with aortic stenosis scheduled for surgical valve replacement who had CMR using our model of incremental addition of imaging acquisitions and intraoperative biopsies. This confirmed that in aortic stenosis patients, measuring ECV in the mid-ventricular wall alone (Model A) showed only a trend towards weak correlation with histological collagen volume fraction (CVF), T1 mapping was used (without post-contrast T1 maps), it is reproducible in healthy volunteers, especially when Model A (one mid-slice), Model C (one mid-slice repeated), Model E , or Model F  are used. Repeating native T1 maps does not appear to offer additional improvement in precision, as Model A performed at least as well as Models C, E and F. Thirdly, both partition coefficient and ECV have been shown to be more accurate than native T1 maps alone. Therefore, we propose that post-Gd imaging (with or without haematocrit sampling) should be routinely undertaken when looking for an estimation of diffuse fibrosis in patients. Fourthly, a single mid-ventricular ECV measurement appears to show poorer correlation with CVF in patients with aortic stenosis (as shown by Model A). Providing additional image repeats, such as model C, E or F for example, appear to show improved correlation with CVF. Although our study is not without its limitations, particularly regarding the use of the CVF as the reference standard, further work could consider whether the additional improvement in correlation provided by models C, E, and F, for example, might be of clinical importance. Finally, the most accurate and precise model is Model F, whereby imaging of one basal and one mid-ventricular level slice, with both being repeated once, is performed both in the native state and after Gd administration.This work therefore supports the following conclusions: firstly, the 11 heart beat MOLLI prototype incorporating native 5b(3b)3b and post-contrast 4b(1b)3b(1b)2b schemes, was well tolerated by volunteers and patients. Secondly, when isolated native T1 mapping routinely in the native and post-contrast state, we recommend that imaging at the same level is repeated once. This will provide additional improvement in the correlation-precision, but also safeguard against potential poor breathholding, poor coregistration, or motion correction in one of the two acquisitions. Such a practical compromise will only increase scanner time by about 30 s. It should be noted that this relation only holds true for the 11HB sequence we have tested, and other MOLLI sequences might not behave in a similar way.We therefore recommend that this should be considered if there is available scanner time and the patients can tolerate it. However, increasing scanner time (even by 5–7 min) might not be possible in many busy CMR units. As such, undertaking repeats of basal and mid-ventricular levels might not be an option. Nonetheless, even in busy units it should be possible to undertake repeat imaging of a single level, which will only add two breathholds to the scan time. Therefore, if a unit undertakes a mid-ventricular slice T1 mapping in our aortic stenosis patients was of very good quality. Furthermore, we elected not to include apical T1 mapping in any of our T1 mapping strategies, as this region is known to suffer increased partial-volume artefact at the endocardial and epicardial borders, which are not perpendicular to the image slice in the apical short-axis region [T1 maps would be taken at different times. In addition, our myocardial biopsies were taken from the apico-lateral wall. Nonetheless, earlier studies have shown that, unlike replacement fibrosis, where there is a significant difference between basal and apical areas [T1/ECV in aortic stenosis including oedema [T1/ECV and CVF should be regarded as an association rather than causative, as there could be multiple aetiologies that might increase T1/ECV.This study has certain limitations. Firstly, our samples for both cohorts were small; however, this is in line with other recently published studies, which also use small (fewer than ten patients) datasets for histological validation , 22. Secs region . Moreoveal areas , interstal areas , 27 in pg oedema  and ischg oedema , 29; theT1 mapping strategies with increasingly inclusive additional imaging for averaging the septal ECV measurements, going from one slice imaged to a total of four images  to improve both the correlation with CVF and the precision of the T1-measurement (both before and after Gd), comparing histological CVF estimation of fibrosis to the T1-mapping outcomes of native T1 maps, partition coefficient and ECV. We have shown that the 11 heartbeat MOLLI sequence used in this research, native 5b(3b)3b with post-contrast 4b(1b)3b(1b)2b, was well-tolerated in both volunteers and patients with aortic stenosis. Furthermore, it was both accurate and precise, particularly as incremental imaging of additional basal and mid-ventricular slice images are included. Finally, this work also confirms that partition coefficient and ECV can be accurately used to correlate with histological CVF estimation of diffuse fibrosis.This work was the first to utilise


Ebstein anomaly is classically considered a malformation of right heart, however, left ventricular is also affected. As LV heart failure is the most common during the natural history, an understanding of heart failure modes is quite significant. Some study have described that the Ebstein's LV basal narrowing, apical modestly dilation, and basal septal dyskinesis but in most ebstein patients the LVEF preserved. The mechanism of the change of LV of Ebstein is not conmon known, but its clinic value draw us searching deeper.So we sought to assess the segmental change in cardiovascular magnetic resonance (CMR) tissue tracking parameters and segmentally quantify Ebstein's LV degree of myocardial diffuse fibrosis by extracelluar volume fraction (ECV), in turn explore the potential mechanism of the LV change15 ebstein patients and 15 age- and sex- matched normal controls were included in current analysis. Three dimensional peak LV strain, peak systolic/circumferential strain-rate, time to peak radial/circumferential strain were measured using 2 chamber (2c), 4 chamber (4c) and stacks of short axis slices in diastolic phase, acquired 16 segments strain, strain rate and time to peak. Subsequently, we manually calculated LV septal/free wall strain and SD time to peak, maximum wall delay and AS-IL time to peak. Segmental ECV were measured on short axis on basal-and mid-ventricular which were corresponding to tissue tracking slices (figure No difference was found between patients and controls at age (29.85 years vs.29.35 years p = 0.769). The radial and circumferential strain were increasing from basal to apical slices in both patients and controls (P < 0.05). Basal septal radial and circumferential strain in Ebstein decreased comparing with controls, but surprisingly, mid and apical septal radial/circumferential strain were larger in Ebstein. Correspondingly, the basal septal ECV were higher than other segmental ECV in patients and all segments in controls (figure FT and ECV are sensitive to document segmental change in cardiac function and histopathology. Additionally, FT and ECV together illustrated that diffuse myocardial fibrosis also existed differential distribution in patients, which negatively related to segmental change in cardiac function. This would be a novel perspective in clinically therapy and prognosis assessment.


Megaptera novaeangliae) has received much research attention. This study focuses on the other baleen whale singer, the bowhead whale . Members of the Spitsbergen bowhead whale population produced 184 different song types over a 3-year period, based on duty-cycled recordings from a site in Fram Strait in the northeast Atlantic. Distinct song types were recorded over short periods, lasting at most some months. This song diversity could be the result of population expansion, or immigration of animals from other populations that are no longer isolated from each other by heavy sea ice. However, this explanation does not account for the within season and annual shifting of song types. Other possible explanations for the extraordinary diversity in songs could be that it results either from weak selection pressure for interspecific identification or for maintenance of song characteristics or, alternatively, from strong pressure for novelty in a small population.Almost all mammals communicate using sound, but few species produce complex songs. Two baleen whales sing complex songs that change annually, though only the humpback whale ( While many mammalian taxa produce repetitive ‘calls’, sometimes called advertisement songs –3, few m) whales –8. With ) whales , complex) whales ,9–11. Ma) whales ,11.The song in baleen whales has been studied extensively only in humpback whales, which sing similar songs within a season across a whole population. The structure of that song gradually evolves over the season in unison  and tranLess is known about the songs of bowhead whales compared with humpback whales, but bowhead whale songs generally consist of a single phrase that includes amplitude- and frequency-modulated elements repeated in bouts, with two different sounds often produced simultaneously . A pilot2.−1 throughout the year. Upon recovery, the data were downloaded and spectrograms  were created for each data file. Spectrograms were then reviewed visually for the presence of bowhead whale songs that were classified by eye based on time-frequency characteristics of each song type [Omni-directional hydrophone recorders were deployed and redeployed annually from 2010 to 2014 in September on a long-term oceanographic mooring in western Fram Strait, at about 78°49 N, 5° W . The mooring deployed in 2011 was not recovered. Instruments recorded acoustic data for the first 14–17 min h3.Bowhead whale songs were detected 24 h per day throughout most of the winter every year . The greatest number of different song types was recorded in December and January . A totalThere was interannual variation in the number and timing of songs. The fewest songs were recorded in 2010–2011 . Both 2012–2013  and 2013–2014  had approximately twice as many different songs .While most song types were short-lived—from hours to days—and seldom lasted longer than a month , every yOf the 3231 recordings containing songs over the 3 years, slightly over half (53%) contained only a single song type, while two different songs occurred in 37% of the recording periods. Less than 10% of all recordings contained more than two different song types.4.The diversity and interannual variability in songs of bowhead whales in this 3-year study are rivalled only by a few species of songbirds . Among oIt is not known whether individual bowhead whales sing multiple song types in a season, but some are known to share the same song type in the same period in the Bering–Chukchi–Beaufort (BCB) population ,16. Nor One explanation for the very high song diversity in the Spitsbergen bowhead whale population could be that the animals occupying this area in modern times include immigrants from both the BCB and the eastern Canada–western Greenland bowhead populations. Until recently, these populations have been assumed to be isolated from each other due to extensive, impenetrable sea ice cover in the High Arctic. However, in the past few decades, extreme declines in sea ice extent and thickness may have facilitated contact between these populations . HoweverIt is plausible that the bowhead whales in the Fram Strait are simply a remnant of the original Spitsbergen population that survived the extreme historical levels of exploitation . The infAlouatta spp.) documented trade-offs in male reproductive characteristics based on (temporary) social structure: in groups with fewer males, or smaller social groups, males invested more in vocal displays as a reproductive tactic [Eubalaena spp.) have enormous testes, are drawn to ‘surface active groups' by a vocalizing female, and lack any apparent male acoustic display [In some species, females appear to prefer a diverse song repertoire –25, sugge tactic . Normall display –29. Howe display .Bowhead whales are the only High Arctic resident baleen whale. Thus, interspecific identification via song may not confer the same selective advantage for bowheads that it might for other cetacean species. This could reduce selection pressure on song stereotypy, allowing for greater variation in song types as a result of a long-term cultural mutation in songs, or song novelty itself might confer an advantage ,20,22,23Because bowhead whales sing underwater, in heavy ice during the polar night, a nuanced understanding of the variable syntax of this species will be difficult to obtain. Nevertheless, the singing behaviour of Spitsbergen bowhead whales, in which tens of distinct song types are produced annually, makes them remarkable among mammals.


Myocardial contrast echocardiography (MCE) has an established role in left ventricular assessment by improving the ventricular opacification and endocardial border definition especially in patients with sub-optimal echocardiographic images. With advances in cardiac ultrasound imaging technology and the development of new contrast agents, the clinical utility of this technique has greatly expanded to include assessment of coronary reperfusion in the setting of acute myocardial infarction, determination of myocardial viability within infarct zones as well as assessment of coronary microcirculation and flow reserve in patients with microvascular coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at peak levels of exercise. Numerous studies have confirmed the clinical utility of contrast enhancement during echocardiographic studies, particularly in patients undergoing stress testing. In this paper, we explore the evidence in support of MCE and its potential clinical applications. Our review aims to summarize (1) the basic principles of myocardial contrast echocardiography including recent advances in the ultrasound technology and contrast agents (2) its clinical applications in the diagnosis of cardiovascular diseases and finally, (3) its potential role in risk stratification and assessment of microvascular perfusion in patients with hypertensive heart disease. Recent developments in contrast agents and acoustic technology have opened new opportunities in the clinical applications of myocardial contrast echocardiography (MCE). Beyond evaluation of cardiac structures and function, MCE can provide much needed insight into myocardial perfusion and thus permit a better understanding of pathophysiologic mechanisms in patients with abnormal LV function. This role appears to have specific advantage in patients with microvascular disease particularly in the absence of concomitant epicardial coronary artery disease. In this paper we briefly describe recent advances in the technology of MCE and potential application of these new advances in the evaluation of patients with hypertensive heart disease.Early use of contrast in echocardiography was necessitated by the need to better visualize cardiac anatomy. Since the initial description of echocardiographic contrast effect in the aortic root by Gramiak and Shah more than four decades ago , signifiTo a large extent the ability of contrast agents to opacify and hence allow the evaluation of the LV has been made possible by the introduction of sonication by Feinstein et al in 1984 . SonicatThe availability of stable microbubbles and the current performance limits of ultrasound imaging and Doppler techniques have encouraged the growth of contrast echocardiography in clinical practice. By increasing the signal to noise ratio, ultrasound contrast agents have greatly improved the sensitivity and specificity of diagnostic ultrasound imaging. Routine clinical applications have been found in the study of myocardial ischemia during functional stress testing, endocardial border delineation and evaluation of valvular flows. Perhaps the most exciting potential clinical utility of contrast echocardiography is in the evaluation of microvascular flows and “no-reflow” phenomenon.®, an earlier generation contrast agent was found to be effective in achieving adequate LV opacification in 81% of cases and improving LV endocardial definition in 83% of patients [Chamber opacification and improved endocardial border delineation allow for accurate assessment of LV volume and hence a more precise estimation of cardiac function. In phase III clinical trials, Albunexpatients . Crouse patients  have alspatients  have dempatients  reported® was the first commercially available contrast agent. Developed by sonication of 5 % albumin solution, Albunex® has excellent myocardial opacification on intracoronary injection but does not opacify left ventricle after intravenous injection [®, FS069 (Optison®) and DMP-115 (Definity)®).The micro-bubbles in these newer generation contrast agents contain larger molecular weight gases with low diffusion capacity thus creating stable bubbles which do not dissolve in blood. They enter the myocardium intact permitting effective backscatter and ultimately satisfactory visualization of the left ventricular cavity as well as the myocardium after intravenous injection thus allowing one to directly evaluate myocardial perfusion [Albunexnjection . After injection . The sigerfusion , 17. Thierfusion , collateerfusion , 20 as werfusion , 21.®), a phase-shift colloid belongs to the newer class of fluorocarbon based ultrasound contrast agents offering better endocardial border delineation and LV opacification. Clinical investigations have thus far shown promise with EchoGen and other new generation contrast agents  in visualization and localization of myocardial perfusion defects at rest by producing a negative contrast effect. Unlike albumin, a less stable contrast agent, the microbubbles produced by EchoGen, Optison and Definity persist in the LV for much of systole and are able to make multiple passes through the portal vein. The microbubbles are small, uniform and stable and thus survive transpulmonary transit, allowing for circulation in the vascular system and enabling imaging of small blood vessels and tissues [Perflenapent emulsion  at 2 years in patients with asymptomatic LV systolic dysfunction , 47. SymIn hypertensive patients with symptoms of heart failure but preserved LV systolic function and no evidence of valvular, pericardial or primary myocardial disease, LV diastolic dysfunction is an important condition and commonly, the culprit. In addition to confirming a normal LV ejection fraction and excluding structural heart disease, the demonstration of abnormal trans-mitral Doppler spectrum is important for echocardiographic diagnosis. However, a pseudo-normal Doppler spectrum may be seen when abnormalities of relaxation, compliance and restrictive physiology coexist. The use of Valsalva maneuver and a careful recording of the pulmonary vein Doppler spectrum can help unmask diastolic dysfunction -56. In pMyocardial contrast echocardiography is an ideal imaging tool for the assessment of coronary microcirculation . MCE canMicrovascular flow may be abnormal in hypertensive heart disease especially in the setting of LVH, and may indeed produce angina symptoms even in the absence of significant epicardial coronary artery disease. By defining the region of abnormal microvascular flow or perfusion with MCE, it is possible to quantify the extent of myocellular damage , 60. TheMyocardial contrast echocardiography is able to demonstrate, not only the presence or absence of microvascular perfusion, but can quantify myocardial blood volume and microvascular reserve , 64. WheCoronary blood flow reserve  is dependent on the inherent vasodilatory properties of the coronary microvasculature  and blooCurrently, only 2 contrast agents (Albunex and Optison) are approved for use in the USA by the Food and Drug Administration (FDA). These agents are approved for the indication of left ventricular opacification and enhanced endocardial border delineation, but not for myocardial perfusion. In line with earlier observations by Marwick et al , review Perhaps, the most promising future application of myocardial contrast echocardiography is in the routine clinical evaluation of myocardial perfusion, coronary, and intramyocardial blood flow. It is expected however that, that with the level of interest and research currently in progress, our understanding of ultrasound-contrast interaction will witness an exponential growth and would spur refinements in machine technology that ultimately will lead to routine clinical application of this technique in patients with microvascular disease such as those with Hypertensive Heart Disease.MCE will undoubtedly continue to gain prominence in the evaluation and management of cardiovascular diseases. It is uniquely positioned to fill a major void in the non-invasive assessment of microvascular flows particularly in patients with hypertensive heart disease and associated co-morbidities. With continued progress and refinements in acoustic technology and contrast agents, these potential applications will soon be translated to routine clinical use.


Hemorrhage is a frequent complication in acute myocardial infarction (AMI) and is speculated to be an independent predictor of adverse outcomes [1]. In addition to infarct zone remodeling, the distal remote myocardium may experience alterations - vasodilator dysfunction, edema, and extracellular matrix (ECM) expansion [2-4]. The aim of our study was to understand the impact of hemorrhage on infarct as well as remote myocardial remodeling following an ischemic event. To this end, we employed quantitative T1 and T2 mapping to probe the underlying tissue alterations in a novel hemorrhagic model of AMI.myo,post-1/T1myo,pre)/. T2 mapping was performed using a T2-prepared spiral sequence. Hemorrhage was assessed from T2* maps obtained using a multi-echo gradient-echo acquisition. Infarcted and remote myocardial segments were evaluated based on LGE images.Hemorrhage was artificially induced in a pig model by direct intracoronary injection of collagenase (col) [5]. Animals (N = 14) were divided into three groups and subjected to an LAD occlusion followed by reperfusion: Group 1 (N = 4) 45 min+saline ; Group 2 (N = 5): 8 min+col; and Group 3 (N = 5): 45 min+col. Imaging was serially performed on a 3T MRI scanner  at baseline  and up to week 4 post-intervention. Pre- and post-contrast T1 values were quantified using a MOLLI sequence. Partition coefficient (λ) was estimated from the relation:. Remote T2 fluctuations were similar to remote zone λ ; group 2 was non-infarcted Figure . Low T2*e Figure . In grou (Figure . Interes (Figure ; T2 showλ Figure ; Remote Our study demonstrates that hemorrhage not only contributes to cellular and microvascular damage and inflammation but may further be responsible for edema and ECM expansion in distal remote myocardium. Early detection of remote tissue alterations will potentially aid better management of the high-risk patients who are prone to adverse long-term consequences.


Right ventricular (RV) end-diastolic volume (EDV) to left ventricular (LV) EDV ratio using cardiovascular magnetic resonance imaging (CMR) is an important parameter for RV size evaluation in additional to indexed EDV. We explore the severity partition for RV dilation using mortality in a population of 62 patients with pulmonary hypertension (PH). Cine short-axis images were acquired with a 1.5 T MR scanner using a steady-state free precession sequence. The optimal cutoff to classify severe RV dilation was determined by a receiver-operating curve (ROC) analysis based on mortality. We further defined mild and moderate categories by the standard deviation distance between normal and severely dilated and found the categories RV dilation by RV/LV volume ratio to be “mild” (1.27–1.69), “moderate” (1.70–2.29) and “severe” (≥2.30). There were significant differences in RVEDV and RV ejection fraction between “mild”, “moderate” and “severe” groups (p < 0.001). The “severe” category had a significantly higher mortality when compared to the “non-severe” categories (p < 0.001) while there was no difference among the “non-severe” dilated groups. We have shown that severe RV dilation partition can be defined using mortality with RV/LV volume ratio, which offers an outcome based grading of the “severe” category of RV dilation. The RV end-diastolic volume indexed to body surface area (BSA) (RVEDVi) is commonly used to quantitatively determine RV enlargement in patients with RV pressure and volume overload4. However, indexing to BSA is not perfect and RVEDVi does not account for the size of the adjacent left ventricle (LV) and may fail to detect dilation in patients with smaller hearts. In light of this limitation, we have shown that RV/LV volume ratio is a more sensitive parameter to detect RV dilation than RVEDVi5. In our previous work5, in a group 152 controls, we determined the normal range of the RV/LV volume ratio to be 0.906 to 1.266, and found that combining this parameter (RV/LV volume ratio ≥1.27) with RVEDVi yielded a higher detection of RV enlargement in a population with pulmonary arterial hypertension (PAH).Cardiovascular magnetic resonance (CMR) has been widely used to evaluate right ventricular (RV) volume and function6. Many cutoff values used in cardiovascular imaging are arbitrarily derived from experience-based consensus of experts in the field or from percentile or standard deviation from normal values in a healthy population7. Ideally, severe abnormality should be determined based on the prediction of risks and prognosis of having that severe abnormality.In the present study, we sought to propose the severity categories of RV dilation based on RV/LV volume ratio. Determining partition values is complicated and most approaches have significant limitationsOur goal is to propose severe RV dilation cutoff values based on mortality risk in a cohort of patients with pulmonary hypertension (PH), a group of diseases that mainly affect the RV.8. All participants gave written informed consent at the time of the CMR. The retrospective review of clinical data was approved by the IRB at University of Pennsylvania and University of Chicago with a waiver of consent. All methods were performed in accordance with our institutional guidelines and regulations.We retrospectively identified 62 PH patients from two institutions (University of Pennsylvania and University of Chicago) who had undergone CMR evaluation with at least 1-year clinical follow-up from the baseline CMR scan or died within 1 year after the CMR. All patients had documented elevated pulmonary arterial pressure and pulmonary vascular resistance and were grouped conforming to the WHO classification of pulmonary hypertension9.Medication list was retrieved from the day of the CMR. Patient records were reviewed for 6-minute walk distance (6MWD) and N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) that were performed within 60 days of the CMR date. The 6-minute walk test (6MWT) was performed according to the recommended guidelines3; TE = 1.05–1.5 ms; TR = 25–35 ms; flip angle = 55–75°; field of view = 280–320 × 280–400 mm2, temporal resolution = 25–35 ms; slice thickness = 8 mm; reconstruction phases = 25–30). Ventricular segmentation was performed using QMASS  by one observer following the Society for Cardiovascular Magnetic Resonance guidelines10. Data from intra- and inter-observer reproducibility were previously published5.CMR images were acquired on a 1.5 T Siemens  or a 1.5 T Philips scanner . Cine short-axis images were obtained using steady-state free precession sequence . Differences between “severe” and “non-severe” categories were analyzed using two-sample, two-tailed Student’s t-test. Cox proportional hazards models were used to investigate the association of the severity of the RV/LV volume ratio and the risk of all-cause mortality. Multivariate analysis was performed with all variables with a p-value less than 0.10 in the univariate analysis. Survival analysis was performed using the Kaplan–Meier method and the log-rank test. A p-value < 0.05 was considered significant.Statistical analysis was performed using SPSS v.23 . The cutoffs for RV enlargement for RVEDVi and RV/LV volume ratio were defined as values higher than two standard deviations (SD) from the mean in a control population: RVEDVi ≥104 ml/m5. We further defined empirically the partition value for “moderate” to be halfway in SD distance from the mean of the “normal” and the “severe” groups. “Mild” group is then determined as > +2 SD of the normal and < moderate.Optimal cutoff value to define severe RV dilation using RV/LV volume ratio was identified using the receiver-operating curve (ROC) analysis. The point with the highest sensitivity and specificity to predict all-cause mortality in our population  was defined as “severe” enlargement. The SD from the mean of the normal control to “severe enlargement” is then calculated. The upper limit of normal was defined as RV/LV volume ratio values ≥2 SD from our control populationThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Fifty-seven patients were classified as group 1 , four were group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)) and one patient was group 5 . Most patients in our study were white females with PAH and were of New York Heart Association (NYHA) functional class II .Comparison of chamber size in end-diastole by RV/LV volume ratio in PH patients with different degrees of RV dilation is shown in Fig. The CMR measurements for the RV according to our severity grading are shown as mean ± SD in Table Survival analysis was performed comparing “severe” vs. “non-severe” groups for all variables. From the eight patients who died during the follow-up period, seven had an RV/LV volume ratio >2.3 and all died due to complications of RV failure. There was one death in a patient with normal RV size (RV/LV ratio <1.27), but it was due to a complication of an abdominal surgery. There was no statistical difference in mortality among the “non-severe” RV/LV volume ratio subgroups (p = 0.45). Event-free survival for the “severe” group was 80% at 1 year, 60% at 2 years, and 45% at 5 years (p < 0.01). Thus, the “severe” category had a statistically significant (p < 0.001) higher mortality when compared to the “non-severe” group Fig. . When co2 , respectively. Event-free survival for the “severe” group according to RVEF , “moderate” (1.70–2.29), and “severe” (≥2.30) are able to successfully distinguish the categories in regard to the degree of RVEF impairment and all-cause mortality in our population. Also, patients in the “severe” category had significantly higher levels of NT-proBNP, which had been shown to be highly sensitive to predict mortality in patients with PH6. However, the prognostic value of these semi-arbitrary categories is not well defined, as the cutoffs are not readily validated in separate cohorts12. For instance, recent guidelines for the diagnosis and treatment of PH established several cutoffs to aid the clinician to stratify the patient into “low”, “intermediate” or “high-risk”13. However, the guideline itself states that “most of the proposed variables and cut-offs are based on expert opinion”13; therefore, these categories may require further investigation to be validated. In our study, we used all-cause mortality in the PH cohort to define “severe” dilation.Most of the partition values used in cardiovascular imaging, such as echocardiography-derived LV size, function, and LA volume, were empirically defined by consensus of experts’ opinions to provide a uniform reference that can be interpreted by clinicians5.All patients classified as “severe” by RVEDVi  were also included in this category by the RV/LV volume ratio. However, the ratio classified 5 more patients into the “severe” group (n = 15) as compared to RVEDVi (n = 10), including an event of death. This shows the higher sensitivity of the “severely increased” RV/LV volume ratio when compared to the “severely increased” RVEDVi (87.5% vs. 75.0%) with a compromise of lower specificity (87.0% vs. 96.0%). Therefore, the RV/LV ratio is better at identifying patients with higher risk of all-cause mortality, but is less specific in predicting all-cause mortality than RVEDVi. Additionally, the same cutoff values of RV/LV volume ratio can be used for both males and females, as there is no significant gender difference in the RV/LV volume ratioet al. found that patients with tetralogy of Fallot (TOF) with a mean baseline RV/LV ratio of 2.2 demonstrated significant improvement in RV volume and function with pulmonary valve replacement3. Studies in the literature assessing RV dilation with pulmonic regurgitation had similar values . Therefore, patients with “non-severe” RV dilation (defined as RV/LV volume ratio <2.2–2.3) are more likely to respond to medical therapy, which may explain the lower long-term mortality in this group.Recent studies on RV volume overload tried to propose cutoff values that integrate the severity of RV dilation and potentially irreversible RV remodeling. For instance, Lee 19. Other CMR-derived functional parameters such as LVEDVi, LV mass, stroke volume index, and pulmonary artery relative area change have been described as prognostic markers in PH21. However, this is the first study to show that RV/LV volume ratio has a strong prognostic value in the evaluation of patients with PH. Moreover, this easily obtained parameter was also shown to predict significant complications related to RV dysfunction in other RV-disease populations such as TOF post-pulmonary valve replacement4.From this perspective, appropriate interpretation of these categories is essential for clinical decision making in order to avoid further deterioration of RV function. Previous studies have already validated RVEF, RVEDVi, RV end-systolic volume index, and RV mass as predictors of mortality in PH patients in accordance with our findings5. All 10 subjects considered as non-dilated RVs by the RVEDVi had “mild” dilation according to the ratio, which supports the idea that the RVEDVi may fail to detect dilation when the RV is enlarged compared to the adjacent LV. Thus, the patient’s LV is a more relevant point of indexing than BSA, because in addition to being representative as a point of reference for the individual, it also accounts for ventricular interdependence22. However, the RVEDVi remains essential for the RV evaluation in patients with biventricular dilation and those with “severely” enlarged RVs (RVEDVi ≥184 ml/m2), as it is a highly specific parameter to predict death since few patients in this category survived more than 24 months of follow-up, as shown in our study (Fig. Finally, we demonstrated that the RV/LV volume ratio improves the detection of RV dilation, which is consistent with our previous findings in a smaller cohortudy Fig. .23. Furthermore, this ratio will not be able to classify patients with biventricular dilation. In which case, RVEDVi alone will have to be relied upon. Larger prospective studies are needed to investigate the value of the RV/LV ratio categories in the long-term monitoring of patients and their responses to therapy.The retrospective design, small cohort size, and small number of events remain the limitations of our study. The cohort was mostly composed of patients with PAH and women, which reflects the female predominance in this diseaseThe RV/LV volume ratio of 2.3 or higher is associated with increased all-cause mortality in a PH population and should be considered as a cutoff for severe RV dilation. RV/LV ratio is an easily obtained, gender-independent, and a sensitive marker of RV dilation.


Non-surgical left atrial appendage occlusion has emerged as an alternative to anticoagulant therapy in the management of stroke risk in patients with atrial fibrillation. This review reports on some of the more common devices that are currently being used to manage patients in this challenging group. Atrial fibrillation (AF) is recognized as the most common supraventricular arrhythmia, and it is known to be a major factor contributing to cardiovascular morbidity and mortality . Among iThe primary modality for stroke prevention in AF patients has been systemic anticoagulation, accomplished for many years with warfarin, and more recently with the introduction of the non-vitamin-K antagonist oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban. While systemic anticoagulation provides effective stroke risk reduction in AF patients, it is subject to several drawbacks, including inconvenience and cost associated with daily medication administration, the need for frequent blood testing and dietary restrictions in patients treated with warfarin, the increased risk of bleeding complications, and the difficulty in management of anticoagulants in the setting of elective or non-elective invasive/surgical procedures or trauma. In addition, therapeutic anticoagulation with warfarin or NOACs preclude the use of intravenous thrombolysis in the case of acute ischemic stroke.As a result of these limitations, mechanical alternatives to anticoagulation for stroke risk reduction have significant appeal and, as such, have been in development for more than 20 years, culminating in approval of the first such device, Boston Scientific’s Watchman, by the US Food and Drug Administration in 2015 . Under tThis article will review the development and current status of LAAO as a therapy for stroke reduction in patients with AF.Proper implantation of left atrial appendage occlusion devices requires pre-procedural assessment of appendage anatomy to guide device selection and deployment. In particular, the size of the appendage’s orifice is used to select the proper device size.Various modalities can be used to assess LAA size and shape, including transesophageal echocardiogram (TEE), cardiac computed tomography (CCT) ,6,7,8, aUsing CCT, Wang et al  describeTEE has also been utilized for pre-procedural assessment of LAA anatomy and for guidance during the implantation procedure. Both multiplane 2D imaging and real-time 3D imaging (RT3D) have been employed. Post-processing of RT3D images can directly measure the LAA orifice area without relying on geometrical assumptions  and is mUtilizing the anatomic information gained from multiplanar CCT imaging with 3D image reconstruction, an algorithm for proper sizing and deployment of the Watchman device has been proposed . Using tIntraprocedural imaging for device deployment is most commonly performed using TEE, which allows for visualization of the left atrium and LAA. Biplane TEE in the 45-degree and 135-degree views provides the most useful images during device deployment, although imaging in views from 0 through 180 degrees is recommended initially to fully assess LAA anatomy. Using TEE, the device position can be evaluated and Doppler interrogation used to assess for para-device leaks. Intracardiac echocardiography (ICE) can also be used for imaging during device implantation, and it has the advantage of potentially eliminating the need for general anesthesia during the procedure as is typically used to allow for TEE imaging . While iFluoroscopic imaging continues to be required during the device implantation procedure itself, during catheter placement, transseptal catheterization, and device deployment. In addition, a pigtail catheter is advanced into the LAA itself to allow cineangiography of the LAA to confirm anatomy and dimensions. Views optimizing measurements of different portions of the LAA have been described . Very exPost-procedural imaging is generally carried out using TEE or more commonly CCT for assessment of LAAO device position and peri-device leaks. Post-procedure CT scanning may be superior to post-procedure TEE in assessing for peri-device leaks, some of which may be missed on TEE due to off axis imaging ,7.2 score of the patient population in a multicenter registry of 64 patients [The first device developed for LAAO was the Percutaneous Left Atrial Appendage Transcatheter Occlusion device, or PLAATO  . This depatients . The devThe Watchman device , seen in The LARIAT device  utilizes an epicardial snaring technique with a pre-tied suture that is used to lasso the LAA and thus occlude the LAA ,21. PlacThe Amplatzer Cardiac Plug , seen in Several other LAAO devices are in earlier stages of development, but none have reached the level of experience and testing of the above devices.There have been several pivotal trials evaluating the efficacy and safety of LAAO devices as compared to warfarin anticoagulation. These studies evaluated LAAO in patients with long term contraindications to warfarin anticoagulation. As mentioned in the earlier section, the Watchman device is the only one with FDA approval and has been the most extensively studied. The first randomized trial evaluating the Watchman device was the PROTECT AF  study reported by Holmes  and collIn the follow-up PREVAIL study  . However, most importantly, hemorrhagic stroke, disabling/fatal stroke, cardiovascular/unexplained death, all causes death, and post procedure bleeding favored the Watchman group .A subsequent meta-analysis  of the PMore recently, there have been studies evaluating the possibility of limiting or implanting the Watchman without post procedural anticoagulation. The recently reported 1-year outcome data from the Ewolution trial , showed Only data in the form of registries exist on the other available forms of LAA occlusion. Other than the Watchman device, there have not been any randomized studies published on other devices used for LAAO. The Amplatzer cardiac plug and its subsequent version, the Amulet, have been approved and available in Europe, but there have not been any published randomized studies on its safety and effectiveness. Registry based studies have been published including the Amplatzer Cardiac Plug Registry  which shAs mentioned earlier, the LARIAT occlusion device is not approved for use as a LAAO device in the US. It requires both endocardial and epicardial access for LAAO which is performed using a snare technique. The device benefits from a theoretical advantage over other devices in that it does not require anticoagulation after implant since the snare is epicardial and is not in the blood pool. However, as demonstrated in multiple small series of patients, leaks are common, and anticoagulation is usually recommended. Two studies from 2014 have shown that the LARIAT device can be used successfully to occlude the LAA, but with elevated risk for complications. In the study published in Heart Rhythm 2014 by Miller et al. , acute sThere are several other devices which are being evaluated to determine their suitability for closing the LAA. The Coherex Wavecrest device was approved for use in Europe, but is no longer available . SeveralNon-pharmacologic treatment of atrial fibrillation associated stroke risk has now been evaluated and shown to be feasible, effective, and safe in patients who have a relative contraindication to long term warfarin anticoagulation. The Watchman device is the only device that has been evaluated in large randomized trials. Ongoing randomized studies are evaluating whether patients can be treated with LAAO and antiplatelet therapy without short term anticoagulation post implant. Multiple other technologies are currently being evaluated to determine whether they also can be used safely and effectively.While LAAO is an important step forward in treating patients with AF in respect to stroke risk, it should also be noted that not all strokes occur from the LAA. In addition, LAAO has not been compared to NOACs, which have a more favorable adverse event profile as compared to that of warfarin. The concept of LAAO has dramatically evolved from a surgical ligation procedure, to a percutaneous procedure that continues to evolve. The role of LAAO in the care of the AF patient remains to be defined.


Cachexia is a prevalent pathological condition associated with chronic heartfailure. Its occurrence predicts increased morbidity and mortality independentof important clinical variables such as age, ventricular function, or heartfailure functional class. The clinical consequences of cachexia are dependent onboth weight loss and systemic inflammation, which accompany cachexiadevelopment. Skeletal muscle wasting is an important component of cachexia; itoften precedes cachexia development and predicts poor outcome in heart failure.Cachexia clinically affects several organs and systems. It is a multifactorialcondition where underlying pathophysiological mechanisms are not completelyunderstood making it difficult to develop specific prevention and treatmenttherapies. Preventive strategies have largely focused on muscle masspreservation. Different treatment options have been described, mostly in smallclinical studies or experimental settings. These include nutritional support,neurohormonal blockade, reducing intestinal bacterial translocation, anemia andiron deficiency treatment, appetite stimulants, immunomodulatory agents,anabolic hormones, and physical exercise regimens. Currently, nonpharmacologicaltherapy such as nutritional support and physical exercise are considered centralto cachexia prevention and treatment. Statistical data from the UnitedStates estimate that 5.7 million Americans over 20 years of age have heart failure;this is expected to increase by approximately 46% between 2012 and 2030, resultingin over 8 million adults with heart failure.2 Following cardiacinjury, the ensuing molecular, structural, and functional ventricular changes areknown as cardiac remodeling. This process is accompanied by cardiac and systemicneurohormonal and inflammatory activation, which adversely affects the heart in avicious cycle and jeopardizes different organs and systems.3 In recent decades, it has becomeclear that pathological changes involve not only the cardiovascular system, but alsothe renal, neuroendocrinological, immunological, hematologic, gastrointestinal, andmusculoskeletal systems, as well as the nutritional status. Currently, experimentaland clinical studies have focused on the physiopathology of heart failure-relatedsystemic complications in order to establish treatments to improve quality of lifeand increase survival.Heart failure is caused by structural and functional abnormalities in the heartleading to impaired ventricular ejection and/or filling capacity. In Brazil, themain causes of heart failure are myocardial ischemia, systemic arterialhypertension, dilated cardiomyopathy and Chagas' disease, and valvedisease.4 We evaluatestudies on heart failure-induced cachexia and discuss different therapies for itsprevention and treatment.Cachexia is a prevalent and important pathological condition associated with chronicheart failure. Its occurrence predicts reduced survival, independent of relevantvariables such as age, heart failure functional class, ejection fraction, andphysical capacity.2) in patients with chronicillness and at least three of the following clinical or laboratory criteria:decreased muscle strength, fatigue, anorexia, low fat-free mass index and abnormalbiochemistry characterized by increased inflammatory markers , anemia (Hb < 12 g/dL), or low serum albumin (< 3.2g/dL).5 As heart failure isan inflammatory disease, Anker et al.6 proposed that cardiac cachexia should be diagnosed when bodyweight loss is > 6% regardless of other criteria and in the absence of othersevere diseases. More recently, investigators have used a body weight loss cutoff> 5% to characterize cardiac cachexia.8 It should be pointedout that cachexia is different from malnutrition or anorexia, which can both easilybe reversed with adequate nutrition.5 Currently, several biomarkers have been studied to help diagnosecardiac cachexia.9 Muscle wastingis an important component of cachexia. It often precedes cachexia development andmay also predict poor outcome in heart failure.10 Differently from cachexia, muscle loss diagnosis depends onthe laboratory evaluation of muscle mass, such as dual energy X-ray absorptiometry(DEXA), computed tomography and magnetic resonance imaging.11 Muscle wasting may also besuggested by poor performance during spiroergometry, 6-min walking test, gait speed,or handgrip strength.11Cachexia has been defined as at least 5% edema-free body weight loss in the previous12 months  in severe cases; this is whenpatients need to be educated on food sodium content. Chronic and vigorous use ofdiuretics can deplete potassium and magnesium levels. With increasedcarbohydrates and amino acids intake and increased insulin levels, there is ashift in potassium, magnesium and phosphorus from extracellular to intracellularcompartments, thus decreasing plasma concentrations of these electrolytes whichcan induce cardiac arrhythmias and sudden death.Non-obese patients with stable heart failure often have inadequate foodintake.44 Intestinalmalabsorption can reduce plasma levels of the soluble vitamins A, D, E, andK.44 As livercongestion and ascites cause food intake intolerance, meals should be frequentand small. It should be stressed that, despite the importance of nutritionalsupport, it has not been established whether adequate protein-energy intake canreverse nutritional status in chronic heart failure.45 Furthermore, increased food intake maycompensate some weight loss, but it can change tissue distribution towardsincreased fat mass, particularly when muscle loss is present.46 Therefore, to preserve orrecover muscle mass, nutritional support should be combined with physicalexercise.There is no specific recommendation for micronutrients in heart failure. Reducedfood intake and chronic use of diuretics can cause water-soluble vitamindeficiency. Thiamine needs particular attention as a deficiency may impaircardiac function.45Supplementation of branched-chain amino acids, which consist of leucine,isoleucine, and valine, preserved body weight, skeletal muscle mass, and cardiacfunction in rats;47 however,it failed to benefit heart failure patients.48Recent small studies have suggested that alterations in specific diet componentsmay be useful in cardiac cachexia. For example, supplements of essential aminoacids improved nutritional and metabolic status in most muscle-depleted heartfailure patients.49 The heart failure control withneurohormonal blockade can reverse cachexia independently of nutritionalsupport.Chronic heart failure is characterized by sustained cardiac and systemicactivation of the renin-angiotensin-aldosterone and adrenergic nervous systemswhich, in the long term, impairs ventricular remodeling. Therefore, blockade ofthese systems is recommended for all heart failure patients with reducedejection fraction.51 Administration of ACEienalapril decreased the risk of weight loss in heart failure patients.6 One may argue that asangiotensin II antagonism improves cardiac remodeling and ventricular function,it would also reduce the risk for cachexia development. Thus, neurohormonalblockade was also examined in cancer cachexia. In tumor-bearing rats,angiotensin and aldosterone antagonism as well as adrenergic nervous systemblockade attenuated body weight and lean mass loss.25 In a phase III clinical trial, ACEi imidaprilprevented weight loss in patients with cachexia caused by non-small cell lungcancer and colorectal cancer but not by pancreatic cancer. When data werecombined however, weight loss prevention did not reach statisticalsignificance.51 Futurestudies are needed to elucidate the role of neurohormonal blockade in differentcauses of cachexia.However, neurohormonal activation is also directly involved in skeletal muscleatrophy. The effects of angiotensin II can be prevented byangiotensin-converting enzyme inhibitors (ACEi) and angiotensin 1 receptorblockers. More recently, angiotensin II has been shown to play a role incachexia and skeletal muscle wasting through different mechanisms such asincreased oxidative stress and protein breakdown; impaired energy balance;reduced appetite via alteration in orexigenic/anorexigenic neuropeptides in thehypothalamus; and inhibition of satellite cell function and muscleregeneration.38 Among echocardiographic parameters, the combination ofright ventricular dysfunction and elevated right atrial pressure provided thebest discrimination between cachectic and non-cachectic patients.52 Furthermore, cardiac cachexiawas associated with intestinal congestion irrespective of heart failure stageand cardiac function.52 Heartfailure patients also have a reduction in intestinal blood flow and an increasein juxtamucosal bacterial growth.53 These abnormalities lead to intestinal bacterialtranslocation and systemic immune activation.54Bacterial endotoxins, also known as lipopolysaccharides, are potent inducers ofpro-inflammatory substances such as tumor necrosis factor (TNF)-α. Asintensive diuretic therapy normalized increased endotoxin levels in heartfailure patients with peripheral edema,54 patients should have as little edema as possible byusing one or a combination of diuretics.49 Despite experimental studies showing antibiotic therapydecreases intestinal bacterial translocation, it is not established whethermicroflora modulation is safe or useful in reducing systemic immune activationin heart failure. Therefore, this approach is not currentlyrecommended.55Heart failure patients with peripheral edema present increased intestine wallthickness, which suggests bowel wall edema.56 Anemia is associated with increased mortality,hospitalization, and impaired quality of life.57 Anemia etiology in heart failure ismultifactorial. Iron deficiency is present in about half of heart failurepatients, independent of the presence of anemia.56 Both anemia and iron deficiency are associatedwith reduced exercise tolerance.58 As decreased exercise capacity is related to a reducedskeletal muscle mass, anemia and iron deficiency may be involved in cachexiadevelopment. Diagnostic evaluation for reversible causes of anemia andsubsequent treatment is appropriate in all patients. Currently, several heartassociations suggest that iron deficiency should be routinely checked in allheart failure patients and corrected if present.56 Intravenous iron preparations are safe andeffective in treating iron deficiency;58 little information is available on the effectiveness oforal iron.56 Intravenous ironcorrection of iron deficiency was associated with improved functionalstatus.59 Aserythropoiesis stimulating agent darbepoetin alpha failed to improve clinicaloutcomes in heart failure patients with mild-to-moderate anemia,60 this class of drug is notrecommended for treating heart failure-associated anemia.The prevalence of anemia in heart failure ranges from 4% to 55%, according tostudy population and anemia definition.Several pharmacological agents have been tested in experimental and clinicalsettings for preventing and treating cardiac cachexia. However, they currentlyrepresent perspectives for the future and are not recommended for clinicaluse.15Although appetite stimulants such as megestrol acetate have been used in othercachectic conditions, they are not approved for cardiac cachexia.Appetite loss is a common finding in cardiac cachexia and its origin ismultifactorial.61 Pentoxyphylline andthalidomide, also considered immunomodulatory agents, were used in small trialswith neutral or favorable results.63 Otherimmunomodulatory drugs such as statins, methotrexate, N-acetylcysteine, T-cellactivation inhibitors, chemokine antagonists, IL-10, and IL-1 receptorantagonists have been tested in experimental studies.64As previously stated, chronic cardiac failure is followed by immunologicactivation, which plays an important role in cachexia development. Therefore,several immunomodulatory agents have been tested in heart failure. Tumornecrosis factor (TNF)-α antagonists etanercept and infliximab were testedin large clinical trials with neutral or negative results.65 Low concentration oftestosterone was related to increased risk of death, independently of leftventricular function or functional capacity.65 In skeletalmuscle, testosterone increases protein synthesis, reduces protein breakdown, andstimulates proliferation and differentiation of satellite cells, thus increasingmuscle mass and strength, and improving exercise capacity.39 Therefore, androgen deficiencymay be involved in the imbalance between anabolic and catabolic processes andcontribute to heart failure-induced muscle wasting and cachexia.65 Testosterone supplementationwas evaluated in small randomized double-blind studies including elderlymen66 andwomen67 with heartfailure. As testosterone improved functional capacity and muscle strength, itwas hypothesized that it could be safe and useful in heart failure and cardiaccachexia.Anabolic hormones have also been examined to preserve and/or increase musclemass. Testosterone levels decrease with age; this phenomenon being faster inheart failure men than in their healthy male counterparts.68 Ghrelin hasbeen evaluated in small trials in different cachectic conditions.15 In heart failure, repeatedGhrelin administration improved exercise capacity and muscle wasting, suggestingthat Ghrelin and its receptor agonist anamorelin may be an attractive approachfor future investigation.69 Growth hormone (GH) also havethe potential to improve muscle mass and functional capacity.70 However, as their effects arenot completely established in heart failure patients,7172 additional research isneeded to clarify the role of GH in cardiac failure and cachexia.Growth hormone release-inducing (Ghrelin) increases adiposity and food intake bymodulating neural circuits that control food intake, energy expenditure, andreward.22Currently, several drugs such as myostatin inhibitors and antagonists,bortezomide (an ubiquitin-proteasome route inhibitor), lipopolysaccharidebioactivity inhibitors, and melanocortin blockers have been investigated withthe purpose of preserving and/or increasing muscle mass in cardiaccachexia.73 Clinical and experimentalstudies have shown that aerobic exercise improves cardiac remodeling andventricular function, and increases functional capacity and quality oflife.76 In skeletal muscle, exercisetraining reduces oxidative stress, activation of the ubiquitin-proteasomesystem, expression of myostatin and proinflammatory cytokines, sympathetic nerveactivity and peripheral vasoconstriction, reestablishes expression of proteinsinvolved in sarcoplasmic calcium handling, and prevents capillary rarefactionand atrophy.79Physical exercise is the most promising option for treating muscle wasting inseveral diseases. Current heart failure guidelines strongly recommend regularphysical exercise for stable patients to prevent and/or attenuate cardiacremodeling and skeletal muscle alterations.48 and a combination ofhydrotherapy with endurance training improved exercise tolerance and hemodynamicprofile of heart failure patients.81 Additionally, high-intensity aerobic exercise was safe andsuperior to moderate-intensity aerobic training in increasing maximal oxygenconsumption.82Therefore, additional studies are needed to establish the best training protocolrelating to exercise type, intensity, duration, and frequency to improveoutcomes in cardiac cachexia.Other exercise modalities have also shown promising results in heart failure. Forexample, a resistance exercise program improved functional capacityCachexia plays an important role in morbidity and mortality in heart failurepatients. Understanding the pathophysiological mechanisms that cause cachexia is anessential step to developing pharmacological and non-pharmacological strategiesaimed at effectively preventing and treating heart failure-induced cachexia beforesignificant body weight and muscle wasting occurs. Currently, nonpharmacologicaltherapy such as nutritional support and physical exercise are the basis for cachexiaprevention and treatment.


Three-dimensional (3D) echocardiography (3DE) and 4-dimensional echocardiography (4DE), also known as real-time (RT) 3DE (RT3DE), are rapidly emerging technologies which have made significant impact in the clinical arena over the years. This review will discuss the recent applications of 3DE in diagnosing and treating different types of cardiovascular disease.Recent studies using 3DE expanded on prior findings and introduced additional applications to different cardiac conditions. Some studies have used 3D parameters to prognosticate long-term outcomes. Numerous innovative software designs including fully automated algorithms have been introduced to better evaluate valvular heart disease and cardiac function.With further evolution of 3DE technologies, this imaging modality will emerge as a powerful tool and likely become the imaging modality of choice in the diagnosis and management of various cardiac disorders. Significant progress in echocardiography has taken place in the last three decades transitioning from M-mode imaging to 2-dimensional (2D) imaging to the emerging role of 3-dimensional (3D) imaging modality. 2D echocardiography (2DE) has made significant impact on the evaluation of various cardiac diseases, and this modality became the clinical guidelines for management of heart disease and an integral part of routine clinical practice. However, 2DE has several well-known limitations, including lack of 3D spatial coordinates, geometric assumptions, apical foreshortening, and limited boundary recognition. Therefore, it became evident that displaying and understanding the complex 3D structures and physiological systems of the human body would be better accomplished using 3D visualization and analysis.The early prototypes of 3D echocardiography (3DE) systems used 2D image acquisitions with free-hand scanning where an external 3D spatial coordinate system was provided by an acoustic spatial locator and using either an acoustic or magnetic system of emitters and receivers that were mounted on the transthoracic imaging transducer; images were acquired and reconstructed offline to create 3D data sets . Using tIn the past 25 years, 3DE has demonstrated to be useful with incremental value or superiority compared to 2DE in various aspects of cardiovascular medicine. This includes accurate measurements of LV volumes, EF, and mass; evaluation of myocardial deformation and regional wall motion analysis; assessment of structure and function of cardiac valves; contribution as a valuable tool pre-, intra-, and post-catheter-based or intra-operative procedures.Numerous studies have validated that RT3DE derived LVEF and LV volume measurements are accurate and reproducible, when compared to CMR and radionuclide scintigraphy. Furthermore, many studies demonstrated superiority of 3DE over 2DE with improved intra-observer, inter-observer, and test–retest variabilities –10. The More recently, studies on 3DE LV chamber function have focused on practicality of this technique and possible integration into routine clinical practice. With 3DE, the limitation is often due to additional time needed to obtain and manually trace the 3D images for LVEF and LV volume calculation as well as lack of 3D experience. Tsang et al. tested the accuracy and feasibility of a novel automated software  that quantifies LV and left atrial volumes and LVEF using 3D transthoracic echocardiography (TTE) data sets with and without manual contour manipulation that are comparable to conventional manually traced 3D measurements and CMR. They concluded that the novel automated algorithm is feasible, reproducible, and timesaving, and such a technique would be necessary to integrate 3DE LV and LA chamber measurements into clinical practice •. Otani Newer approach for assessing blood flows within the LV using fully automated software has also been reported. Thavendiranathan et al. used the velocity information encoded in the volume color Doppler data together with simultaneous RT3D TTE imaging of the mitral annulus and the left ventricular outflow tract (LVOT) to quantify mitral inflow and aortic stroke volumes in the same cardiac cycle. There was excellent correlation between these automated measured values with CMR stroke volumes. They also found that this automated technique is rapid, feasible, reproducible, and accurate for measuring mitral inflow and aortic stroke volumes and is superior to manual 2D TTE-based measurements. They concluded that this method may be practical in routine practice to measure stroke volumes, regurgitant volumes, and cardiac shunt fractions .Furthermore, recent studies have also focused on outcome data. Stanton et al. studied 455 patients who underwent LV assessment with 2D and 3D TTE and found that 3D LVEF and 3D LV end systolic volume were the strongest predictors of outcomes  than any of the 2D TTE parameters over a follow-up of 6.6 ± 3.4 years •. GriparNumerous studies have demonstrated that LV performance can also be assessed by myocardial deformation or strain, which can be performed by a technique known as speckle-tracking echocardiography (STE). This technique uses a pattern-matching algorithm and permits tracking through space and time of all anatomic features including the myocardium present in the echocardiographic image. While 2D STE is limited due to difficulties in tracking the speckles when the speckles move in and out of the 2D imaging plane, 3D STE overcomes this limitation.Using 3D STE, studies have shown that LV volume assessment is more accurate and reproducible compared to 2D STE . 3D STE The Framingham Heart Study as well as other studies have shown that elevated LV mass is a strong, independent predictor of cardiac events and death . InitialStudies have shown that 3DE reconstruction is useful in determining measures to assess LV remodeling beyond LV mass, including analyzing LV endocardial surface area, infarct subtended surface area, and infarct subtended volume and volume/mass ratio. This is accomplished by calculating a 3D surface area/volume ratio and indexing it to a surface area/volume ratio of a sphere. As the LV undergoes adverse LV remodeling and becomes more globular and spherical, the sphericity index increases .LV volume can be further broken down into 16 or 17 regional segments, and volume in each of these segments can be tracked over the full cardiac cycle to generate time-volume curves. In addition, a bull’s-eye plot can be made of time-volume curves which are generated from the entire LV surface. These time-volume curves and plot can be color-coded to show differential segment contraction . These tools may be useful in evaluating a patient for a biventricular pacemaker. Furthermore, regional volumes assessed in a group of patients were compared against CMR as a reference; agreement levels were very high in basal and mid-ventricular segments, but lower near the apex. This difference may be due to limited endocardial definition near the apex on both 3DE and short axis CMR images affected by partial volume artifacts in this region . RT3DE aTest–retest variability is a measure to assess the utility of a test to assess a parameter in a serial manner. The lower test–retest variability of 3DE compared to 2DE has been well established. In patients undergoing sequential LVEF and volume quantification during cancer chemotherapy, accurate and reproducible quantification of these measures with the lowest temporal variability is vital for clinical decision-making. Marwick et al. found that in patients with stable function while undergoing chemotherapy for breast cancer, non-contrast 3DE was the most reproducible method for LV volume and LVEF measurements over 1 year of follow-up. In addition, 3DE showed the best intra-observer, inter-observer, and test–retest variabilities .One potential valuable use of 3DE LV quantification is for risk stratification of patients with moderate LV dysfunction post-myocardial infarction (post-MI) or heart failure to guide management with offering lifesaving treatment, i.e., implantable defibrillator placement and/or biventricular pacemaker, based on the post-MI EF. Gopal et al. risk stratified routine methods  compared to 3DE and CMR in patients with myocardial infarction or congestive heart failure and EF ≤ 40%. 3DE had the lowest misclassification rate, stronger correlation, and less bias than 2DE. Based on analysis of variance, 3DE but not 2DE was equivalent to CMR. This study showed that routine methods are inadequate and 3DE is superior for risk stratification by EF post-MI. Furthermore, 3DE with threefold lower test–retest variability than 2DE establishes its use for serial monitoring .Accurate determination of RV size and function is important for management of various disease processes, including congenital heart disease, pulmonary hypertension, myocardial infarction, heart failure, and pulmonary embolism. Thus, an accurate and easily repeated noninvasive imaging modality for serial evaluation of patients would be essential. However, noninvasive assessment of RV structure and function based on 2D geometric modeling has been challenging due to its complex crescent shape consisting of the inflow tract, the infundibulum, and the apex which are often not all visible simultaneously using 2D imaging techniques. Its retrosternal location also causes suboptimal image quality. In addition, RV myocardial fiber arrangement is different from the LV resulting in peristaltic contractile function. This difference prevents the application of established echocardiographic methods for LV function to assess the RV function .Given the prognostic importance of RV dilatation and function in various disease states, different imaging modalities have attempted to better evaluate the RV. CMR has become the gold standard due to its ability to quantitate RVEF and volumes without concerns of geometric assumptions. Although 2D echocardiographic parameters of RV function, including tricuspid annular plane systolic excursion (TAPSE), basal RV free wall tissue velocity, and fractional area change (FAC), have been established and validated against CMR, technical limitations remain.Some of the earlier 3D TTE studies showed underestimation of RV volumes and EF compared to CMR  or that Echocardiography is the main imaging modality for diagnosing and managing patients with valvular heart disease . NumerouThe mitral valve (MV) apparatus is a complex structure which consists of the leaflets, the saddle-shaped annulus, the chordae tendineae, and the papillary muscles. 3DE has significantly contributed to the anatomic and mechanistic understanding of the MV apparatus in the setting of normal function and dysfunctional pathologic states , 45. SpeSeveral recent studies of the MV and its apparatus utilizing RT3D TEE have provided additional information to our understanding of its structure and function. Zeng et al. assessed the geometry of the MV with different tethering patterns (asymmetric and symmetric) using RT3D TEE to determine the impact on ischemic mitral regurgitation (IMR) severity based on the tethering patterns. They studied 62 patients with at least moderate IMR and found that (1) there are quantitative differences in MV geometry depending on the tethering patterns, (2) the tethering pattern and the total degree of tethering affects IMR severity, and (3) independent of reduced mitral annular dilatation and higher LV function, asymmetric tethering pattern results in increased severity of MR . Yuan etFurthermore, some groups have utilized novel semi-automated algorithm with RT3D TEE, i.e., anatomical intelligence in ultrasound (AIUS), and concluded that this technique improves accuracy and efficiency in localizing mitral valve prolapse . Aquila With 3DE, color Doppler evaluation as well as anatomic regurgitant orifice area can be assessed and improve the accuracy of diagnosing regurgitant lesion severity. Visualization of the regurgitant jets, including the eccentric jets, is feasible and quantifiable in most patients with RT3D TEE. Also, it has previously been demonstrated that vena contracta area (VCA), effective regurgitant orifice area (EROA), and regurgitant volumes (RV) can be accurately measured with RT3D TEE. Recently, novel approaches and softwares using automatic 3D color Doppler have been utilized to better quantify MR. Heo et al. demonstrated that automatic quantitation of MR using 3D full volume color Doppler TTE was superior to 2D full volume color Doppler TTE, as compared with CMR . In addiThe aortic valve is part of the aortic root structure which also consists of the sinus of Valsalva and the inter-leaflet triangles . NumerouRecently, Caballero et al. showed that many patients with aortic stenosis (AS) have an elliptical and funnel-shaped LVOT which is more prominent further from the annular plane, and measuring 2D LVOT dimension closer to the annular plane best correlates with 3D measurements . MehrotrWhile numerous studies have assessed the role of 2D STE imaging in aortic stenosis, limited number of 3D STE studies has been performed. In a recent study with 104 asymptomatic severe AS patients with preserved LVEF, 3D global longitudinal strain (GLS) was the strongest predictor for future adverse cardiac events over a follow-up of 373 days .3DE has shown to have incremental value over 2DE in the assessment of the tricuspid valve (TV) structure and function. It is well established that the standard 2D views of the TV  can only visualize two of the three TV leaflets. Furthermore, there is significant variability as to which leaflets are being seen in these views. Addetia et al., using 3D multiplanar reconstruction method, found nonstandard 2D views which can better identify the TV leaflets .In the setting of pacemaker leads, 3DE is useful in identifying the position of the lead as it crosses the TV and improves the assessment of tricuspid regurgitation (TR). Addetia et al. studied the impact of implantable transvenous device lead location on the severity of TR and found that 3D TTE is superior to 2D TTE in identifying lead-leaflet interference which results in TR after device lead placement. This finding suggests 3D TTE should be considered in the evaluation for possible lead interference in patients with significant TR after lead placement. Furthermore, TR quantification using 3D color Doppler VCA is feasible and shows good correlation with 2D methods . For funRT3D TEE is known to accurately evaluate prosthetic valve function with better visualization of the prosthetic valve anatomy as well as potential paravalvular regurgitation or vegetation. Thus, this modality plays an important role during transcatheter interventions for treatment of paravalvular regurgitation  or bioprWith rapidly expanding catheter-based procedures for treatment of structural heart disease, RT3D TEE is known to be a powerful imaging modality for pre-procedural evaluation, intra-procedural guidance, and post-procedural assessment. During the catheter-based procedures, the main advantages of RT3D TEE are the ability to visualize (1) in real time the structure and pathology undergoing intervention in “en-face” view, which is not possible with other imaging modalities, and (2) the intra-cardiac catheters, including the tips and the devices or balloon that are carried, as well as their position relative to the surrounding structures .Since the acceptance of TAVR as an alternative to surgical treatment, this technology has been rapidly expanding and the value of RT3D TEE became well established with this procedure. Recent studies have shown that RT3D TEE plays a vital role in determining the size of the transcatheter valve , 70. FurRT3D TEE has also shown to play an important role with MitraClip implantation . CompariIn order to enhance 3DE applications into routine clinical practice, further improvement in transducer technology as well as software and machinery development are warranted. Especially with 3D TTE, the improvement of temporal and spatial resolution would significantly expand its utility for various disease processes and integrate routine 3D imaging as part of 2D TTE imaging. Improvement in 3D color Doppler technology as well as software development will permit novel ways to analyze structure and function. In addition, standardization of various platforms and algorithms among vendors is necessary in order to develop long-term RT3DE prognostic parameters. Lastly, use of fusion imaging incorporating RT3DE with other modalities may provide incremental value in diagnosis and treatment of various cardiac diseases.The field of 3DE has made tremendous progress since its introduction three decades ago. Recently, RT3D TEE has demonstrated to play a vital role particularly in the diagnosis and management of valvular heart disease. With further advancement of the 3D technology with improvement in transducer technology, image quality, standardization, and software development, it is anticipated that 3DE will progressively become more integrated into the clinical guidelines and routine practice.