The myocardial adaptive mechanism in patients with repaired tetralogy of Fallot (rTOF) is less understood. We aimed to investigate biventricular myocardial adaptive remodeling in rTOF patients.RVPA). rTOF patients with PGRVPA < 15 mmHg and ≥15 mmHg were classified as low pulmonary stenosis  and high pulmonary stenosis  subgroups, respectively. Magnetic resonance imaging tissue phase mapping was employed to evaluate the voxelwise biventricular myocardial motion in longitudinal (Vz), radial (Vr), and circumferential (Vφ) directions.We recruited 32 rTOF patients and 38 age- and sex-matched normal controls. The pulmonary stenosis of rTOF patients was measured using catheterized pressure gradient between right ventricle (RV) and pulmonary artery (PGlow subgroup presented higher pulmonary regurgitation fraction than rTOFhigh subgroup (p < 0.001). Compared with the normal group, only rTOFlow subgroup presented a decreased RV ejection fraction (RVEF) (p < 0.05). The rTOFlow subgroup showed decreased systolic and diastolic Vz in RV and LV, whereas rTOFhigh subgroup showed such change only in RV. In rTOFlow subgroup, RVEF significantly correlated with RV systolic Vr , whereas LVEF correlated with LV systolic Vz . Prolonged QRS correlated with RV systolic Vr  and LV diastolic Vr . No such correlations occurred in rTOFhigh subgroup.The rTOFhigh subgroup suggested that adequate pulmonary stenosis (PGRVPA ≥ 15 mmHg in this sereis) has a protective effect against pulmonary regurgitation.The avoidance of unfavorable functional interaction in RV and LV in rTOF RVPA). Studies have observed that an adequate PGRVPA can serve as a protective factor limiting the unfavorable effect of PR on RV function in rTOF patients [Pulmonary regurgitation (PR) is an important problematic sequel in patients after repair of tetralogy of Fallot (rTOF). Although PR can be tolerated for many years, chronic PR can lead to right ventricular (RV) volume overload, hypertrophy, fibrosis, myocardial injury, and heart failure overtime –4. In adpatients –13.Cardiac magnetic resonance imaging (MRI) is the standard method for comprehensive evaluation of rTOF patients –3,6,14. RVPA was measured to differentiate rTOF patients with low and high PS. We aimed to investigate the biventricular myocardial adaptive mechanisms on account of residual PS in rTOF patients using TPM from mechanistic insights.In this case–control study, the catheterization-based PGThis study protocol was approved by the ethics committee at Kaohsiung Veterans General Hospital, Kaohsiung (VGHKS14-CT1-16), Taiwan and all procedures were in accordance with the ethical standards of the institutional and research committees. All participants provided written informed consent prior to cardiac MRI examination. The study population consisted of 32 rTOF patients  and 38 normal controls  without known cardiovascular diseases. The rTOF patients underwent electrocardiography (ECG), treadmill, blood sampling for brain natriuretic peptide (BNP) measurement, and catheterization for assessment of hemodynamic status. The rTOF patients and normal controls were subjected to cardiac MRI examination. The datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.RVPA, we defined rTOF patients with PGRVPA< 15 mmHg as the subgroup with low PS (rTOFlow) and rTOF patients with PGRVPA ≥ 15 mmHg as the subgroup with high PS (rTOFhigh). The surgical procedure of transannular patch was performed on 12 of 19 and 8 of 13 patients in rTOFlow and rTOFhigh subgroups, respectively.Catheterization-based cutoff value of 15 mmHg based on PR of 40% in a receiver operating characteristic analysis was selected in this series. According to the cutoff value of PGRVPA was also recorded. All pressures measurements were taken in the supine position and at end-expiration.The normal controls did not undergo catheterization.A 7 F Berman catheter was inserted into a femoral vein and a 5 F pig-tail catheter was inserted into the femoral artery when rTOF patients underwent catheterization. Both catheters were connected to pressure transducers. A Berman catheter was advanced into the right atrium, RV, and main PA to measure pressure. The PG2) was measured from the results of a graded treadmill exercise until exhaustion. Blood pressure (BP) and heart rate (HR) were also measured during resting and peak state. HR reserve (HRR) was defined as the HR change between 1 minute after test and peak state during test. The metabolic equivalent (MET) of peak VO2 was defined as the unit of resting oxygen uptake. The BNP level was measured using commercial ARCHITECT BNP Reagent Kits (Abbott Laboratories).The rTOF patients underwent an exercise stress test on a treadmill with the standard Bruce protocol . An exer2, slice thickness = 6 mm, interslice gap = 4mm, and flip angle = 50°. Consecutive 10–12 short-axis views covering the entire LV and RV enabled determination of the cardiac function, including the volumetric indices, mass, and ejection fraction (EF).Images were acquired using a 3-T MR scanner . A retrospective ECG-gating approach was used to acquire two-dimensional breath-hold steady-state free precession based cine images in short-axis view with 30 time frames per cardiac cycle. The protocol parameters were as follows: TR/TE = 3.1/1.6ms, pixel size = 1.17 × 1.17 mmThe two-dimensional phase-contrast MRI in this study was performed with retrospective ECG triggering and free breathing to calculate the PR fraction, which was defined as backward flow volume divided by forward flow volume. The scanning parameters were as follows: TR/TE = 9.9/2.7 ms, flip angle = 30°, matrix size = 192 × 174 (interpolated into 256 × 256), field of view = 24–32 cm, slice thickness = 6 mm, views per segment = 2, and average = 2. Forty phases per cardiac cycle were reconstructed. Velocity encoding was initially set at 150 cm/s and increased by 100 cm/s if an aliasing artifact was present. The main PA was targeted at its midpoint between the pulmonary valve and bifurcation. The imaging planes were prescribed as strictly perpendicular to the vessels by using the double-oblique technique.2, slice thickness = 6 mm, flip angle = 7°, acceleration factor = 5 with the PEAK-GRAPPA accelerating technique [A two-dimensional dark-blood fast low-angle shot sequence was performed to acquire TPM. Images were prescribed in consecutive three short-axis slices . The basal slice was prescribed at 1cm beneath the mitral valve level at end-systole, followed consecutively by middle and apical slices. Prospective ECG-triggering was performed for synchronization with the cardiac motions. Navigator-echo monitoring was performed to trace the location of the right hemidiaphragm. Velocity encoding was set to 15 and 25 cm/s for in-plane and through-plane motions, respectively. The protocol parameters were as follows: TR/TE = 6.5/4.2 ms, pixel size = 1.17×1.17 mmechnique , and temThe myocardial motion was calculated using aninstitute-developed analysis tool written in MATLAB (Mathworks). After regions of interest had been determined manually on the magnitude images of each cardiac phase and each slice, the LV was divided into 16 segments according to American Heart Association recommendations , whereasRVPA for the classification of rTOF patients into rTOFlow and rTOFhigh subgroups. Intra-observer and inter-observer variability was assessed in 10 rTOF patients and 10 normal controls. Inter-observer and intra-observer variability of TPM parameters was evaluated using the intraclass correlation coefficient (ICC). P < 0.05 was considered statistically significant.The statistical significance of the difference between groups was assessed using ANOVA analysis or Fisher exact test when appropriate. The Pearson correlation coefficient was calculated for the relationship between any two interested parameters. Multiple comparisons using Bonferroni correction for the LV 16-segment and RV 10-segment model were performed to examine the significance of the altered myocardial motion. Receiver operating characteristic analysis was used to seek the cut-off value of the PG2 than the regular standards reported by a previous study [low and rTOFhigh subgroups were substantially higher than the reported regular standards [us study . The othtandards .low and rTOFhigh subgroups presented significantly higher PR fractions than normal group (both p < 0.001). Moreover, PR fraction in rTOFlow subgroup was higher than that in rTOFhigh subgroup (p < 0.001). Compared with normal controls, rTOFlow subgroup exhibited increases in most RV volumetric indices  and significant decreases in RVEF (p < 0.01). For the LV, the volumetric indices were similar in all groups, whereas the LV end systolic volume index decreased and LVEF increased only in rTOFhigh subgroup (both p < 0.05).p < 0.001), particularly in the basal and middle slices (p < 0.001) and lower LV diastolic Vz . Regarding the radial myocardial motion, only the RV diastolic Vr in the rTOF group was higher than that in the normal group . Decreased systolic and diastolic Vφ (i.e. the second peak during systole) were noted only in the LV of rTOF patients (p < 0.001). All the aforementioned indices did not differ significantly between rTOFlow and rTOFhigh subgroups.e slices . The rTOlow subgroup, the PR fraction showed significantly negative correlations with PGRVPA . However, only QRS duration in rTOFlow subgroup was significantly negatively correlated with RV systolic Vr  were observed solely in rTOFting TOF –13 and rValente et al previously reported that PR and RV volume were not related to early death or ventricular tachycardia in rTOF patients . Howeverlow subgroup decreased in both RV and LV, whereas myocardial motion in rTOFhigh subgroup decreased in RV and was normal in LV. This may suggest that LV adaption was secondary to RV changes with the progression of RV dysfunction.TPM has the advantages of high spatial resolution and direct three-directional measurements of myocardial motion. This technique has been used to demonstrate that rTOF patients may exhibit RV myocardial motion abnormality owing to excess stress in response to volume overload ,6,14. Welow subgroup. RVEF closely correlated with RV systolic Vr, whereas LVEF closely correlated with LV systolic Vz. The discrepancy between RV and LV adaption may be partially explained by the different inherent but integrative myofiber architectures in the two ventricles and also by a substantial adaptive increased thickness of the circumferential layer found histopathologically in the RV of rTOF patients [We found that differential myocardial motion adaption underlined RV and LV remodeling in rTOFpatients ,28. In apatients .low subgroup. These findings suggested that altered myocardial radial motion, either in RV or LV, may underscore the adverse effect of QRS prolongation in rTOF patients without protection from adequate residual PS [We found prolonged QRS durations in both rTOF subgroups. Electromechanical interaction with prolonged QRS duration has been described as a predictor of ventricular arrhythmias in rTOF patients ,29,30. Hidual PS ,9,31.high patients, RVEF and LVEF are both preload- and afterload-dependent, and thus are not tied physiologically. The presence of biventricular EF correlation in rTOFlow subgroup may imply an unfavorable effect of RV on LV, and thus may also reflect the deteriorated cardiac function in rTOF patients without adequate PS. The myocardial longitudinal motion of RV and LV was disclosed to be significantly correlated in all subjects, independent of the rTOF status. The role of myocardial longitudinal motion correlation between RV and LV requires future investigation.In a scintigraphy study of 152 patients, Movahed et al demonstrated that there was a strong significant correlation between LVEF and RVEF in patients with decreased EF, but no correlation was found in patients with normal EF . This phAlthough we showed the decreased LV Vφ during systole in rTOF patients compared with that of normal controls, it should be noted that the assessment of circumferential myocardial motion was more difficult to identify compared with longitudinal and radial motion ,24. Furthigh subgroup suggested that adequate PS (PGRVPA ≥ 15 mmHg in this series) has a protective effect against PR in the ventricular remodeling of rTOF. Our findings shed light on the mechanical and electrical adaptation in both RV and LV of rTOF patients and potentially provide helpful information for surgical strategy in treating patients with TOF. A larger and longer cohort study is required to investigate the prognostic value of our findings in evaluation of rTOF patients.In conclusion, this study explored the adaptation of biventricular function and the differential myocardial motion components in rTOF patients in response to residual PS. From a mechanistic insight of myocardial motion adaptation, avoidance of unfavorable functional interaction in RV and LV in rTOF2, which was consistent with the spatial resolution of a highly ranked previous study on TPM of RV [This study had some limitations. First, the thin wall of RV may have rendered the reliability of RV delineation in the TPM images. However, we acquired TPM images with a pixel size of 1.17 × 1.17 mmPM of RV . Second,S1 File(DOCX)Click here for additional data file.


Journal of Thoracic and Cardiovascular Surgery. At that time most described the group of lesions as ‘atrioventricular canal malformation’ or ‘endocardial cushion defect’. Perhaps more significantly, the so-called ostium primum defect was thought to represent a partial variant. It was also universally thought, at that time, that the left atrioventricular valve was no more than a mitral valve with a cleft in the aortic leaflet. In addition to this, lesions such as isolated cleft of the mitral valve, large ventricular septal defects opening to the inlet of the right and hearts with straddling or overriding tricuspid valve were variations of the atrioventricular canal malformation. Anderson and Becker emphasised the differences between the atrioventricular junction in the normal heart and those with a common junction for which they recommended the generic name, ‘atrioventricular septal defect’. As I will discuss, over many years, they continued to work with clinical cardiologists and cardiac surgeons to refine diagnostic criteria and transform the classification and understanding of this complex group of anomalies. Their emphasis was always on accurate diagnosis and communication, which is conveyed in this review.Robert Anderson has made a huge contribution to almost all aspects of morphology and understanding of congenital cardiac malformations, none more so than the group of anomalies that many of those in the practice of paediatric cardiology and adult congenital heart disease now call ‘Atrioventricular Septal Defect’ (AVSD). In 1982, with Anton Becker working in Amsterdam, their hallmark ‘What’s in a name?’ editorial was published in the  Robert Anderson has made a huge contribution to almost all aspects of morphology and understanding of congenital cardiac malformations, none more so than the group of anomalies that many of those in the practice of paediatric cardiology and adult congenital heart disease now call ‘Atrioventricular Septal Defect’ (AVSD). In 1982, with Anton Becker working in Amsterdam, their hallmark ‘What’s in a name?’ editorial was published in the Journal of Thoracic and Cardiovascular Surgery [Prior to that groundbreaking publication, it was already recognised that a group of malformations had comparable morphology comprising abnormal atrioventricular valves. Blieden and colleagues  had prevThere were two extremely important events contributing to the breakthrough in understanding. The first was when Anderson and Becker, working with heart specimens in Amsterdam, stripped away completely from the atrioventricular junction, the leaflets of the atrioventricular valves. Having removed the valve leaflets, it was realised that in any individual heart with this group of anomalies, it was impossible to know whether, initially, the specimen had represented a so-called ‘partial’, ‘intermediate’ or ‘complete’ example of the anatomy, because each of the hearts had a common atrioventricular junction completely different from the normal heart. The second important event was when cardiologists, using their newly acquired skills in cross-sectional echocardiography, were able to produce exquisite moving images of these hearts, representing cross-sectional anatomic sections. I recall Bob Anderson being ‘blown away’ by what he was seeing at our regular weekly meetings and immediately our understanding began to reach completion. With morphological sections of the heart , he simuBy coincidence, in 1982 we were both guests of the Brazilian Society of Pediatric Cardiology in Porto Alegre around the time of publication. During this, my first visit to South America  it was nConsidering first the normal atrioventricular junction , it is dIn essence, Anderson and Becker had proposed the term ‘atrioventricular septal defect’ as a generic name for a group of anomalies characterised by absence of atrioventricular septal structures and consequently possessing a common atrioventricular junction guarded by a common atrioventricular valve and therefore completely different from the atrioventricular junction of the normal heart . There iIn almost every form, the common atrioventricular valve is composed of five leaflets of which only the superior and inferior bridging leaflets are found within both the left and right ventricles, whereas the left mural leaflet is confined to the left ventricle and the right (inferior) mural and right anterosuperior leaflets are located inferiorly and antero-superiorly, respectively, in the right ventricle. The zone of apposition of the inferior and superior bridging leaflets is the most frequent site of valve insufficiency. This common valve will have a single (‘common’) orifice or will be divided into two orifices by a tongue of valve tissue joining the bridging leaflets; this provides the basis for a broad classification of all cases a,b. Irrep < 0.001 in Table III of that publication. So, it seems to me that it could indeed be a diagnostic criterion on its own.With two valve orifices the most frequent form is the isolated primum defect, which is also commonly described as ‘partial AVSD’, although there is nothing partial about the common atrioventricular junction, which is just as complete as that seen in patients with common valve orifice. Other variations include an isolated interventricular defect or combined primum interatrial defect and interventricular component; both forms can also be described as ‘intermediate’, but qualifying additional description is required in diagnosis to distinguish the two forms. Rarely are completely intact septal structures found, an AVSD without interatrial or interventricular communication. With common orifice the main variation is found in the degree of bridging of the superior bridging leaflet, but there is almost always an interatrial and interventricular communication. Whatever the type of AVSD, the left ventricular outflow is sometimes longer than that of the normal heart , and theQuite independent of these various types, associated anomalies can include left or right ventricular inflow obstruction, dual orifice left ventricular atrioventricular valve leaflets, atrioventricular valve regurgitation, left or right ventricular outflow tract obstruction in various forms, and right or left ventricular hypoplasia . Left ventricular outflow obstruction can be particularly complex. The subaortic outflow is frequently elongated and relatively narrow in all forms of AVSD. The causes of obstruction include anomalous tissue tags, anomalous chords to the ventricular septum, discrete fibromuscular stenosis and tunnel-like narrowing. Another variation to be aware of is double outlet right atrium, in which inevitably blood flows directly from right atrium to left ventricle, causing unexplained systemic arterial desaturation. There is also a well-recognised association of AVSD with Trisomy 21, atrial isomerism, total anomalous pulmonary venous connection and Tetralogy of Fallot and, rarely, even with common arterial trunk.The key to the diagnosis of AVSD and, to a major extent, appropriate and effective surgical management lies in the structure of the atrioventricular valve leaflets found in the left ventricle ,10. WhenThere is a potentially complicating aspect when the left ventricular valve leaflets lack the usual morphology found in an AVSD, and this also has major surgical significance ,12. The It is important briefly to discuss a rare form of deficient atrioventricular septation with separate left and right atrioventricular junctions. The patients with deficiency of the fibrous atrioventricular septum, although properly described as atrioventricular septal defects, do not have a common atrioventricular junction. It was the view of Anderson that it was more convenient to describe them as ‘Gerbode’ defects while recognising their affinity with hearts with perimembranous VSD combined with the potential for ventriculo-atrial shunting because of a deficiency in the commissure between the septal and anterior leaflets of the tricuspid valve.The diagnosis of any form of AVSD is almost always made by cross-sectional echocardiography, which provides exquisite imaging and a precise diagnosis in most cases, particularly in early life ,7; magneThere are some basic rules of cross-sectional echocardiography that are fundamental to the diagnosis ,7. The sIt is important to be aware that the typical trileaflet appearance of the left ventricular valve is distorted when there is a dual orifice or severe leaflet dysplasia . A two-lThe mainstay of diagnosis remains cross-sectional echocardiography ,7. The mThe typical features of the so-called ‘complete’ AVSD are also best identified in four chamber sections and include a primum interatrial defect, common atrioventricular valve orifice and an interventricular communication that can be more or less extensive, depending on the attachment of bridging leaflets . The infSo, what is in a name when today’s cardiovascular imaging is so good? In many situations, the exquisite detail provided by echocardiography cannot be described in a single word or phrase, although in most cases there is a primary diagnosis that alerts physicians and surgeons to the basic abnormality . ConsideBut what of hearts with a common atrioventricular junction and common orifice (‘complete AVSD’)? Such examples are often called ‘atrioventricular septal defect’ as the primary diagnosis. This is clearly an unsatisfactory state of affairs taking into account that this is the selected generic name for all types, but the terms ‘complete atrioventricular septal defect’ or even ‘complete atrioventricular canal defect’, although imperfect, are still better able to convey a diagnosis that everyone understands. To my mind ‘atrioventricular septal defect with common valve orifice’ is too much of a mouthful. Any additional abnormalities such as left or right ventricular hypoplasia  can be recorded as additional secondary diagnoses.‘Isolated primum ASD’ or ‘partial AVSD’,‘AVSD with two valve orifices and isolated ventricular component’ or ‘AVSD with isolated VSD’,‘AVSD with two valve orifices, primum ASD and small ventricular component’ or ‘intermediate AVSD with primum ASD and VSD’,‘Complete AVSD’,‘AVSD with intact septal structures’.So, what should we call the various types of AVSD? Always, the underlying principle is precise and accurate communication. I would suggest ‘complete AVSD’ is a term understood and accepted as referring to hearts with a common valve orifice and primum and interventricular defects. I would also advocate that the terms ‘partial’ or ‘incomplete’ refer to all types of AVSD with two valve orifices and isolated primum defect while ‘intermediate’ refers to any AVSD with two valve orifices and an interventricular communication. However, in the nomenclature of CHD  recently designed by the ISNPCHD for the ICD-11 , the terThis basic classification can be used when there are deviations from the usual forms, such as ventricular hypoplasia ,14,15,16Problems in nomenclature can also arise in some hearts with AVSD because there is a profound departure from the usual morphology. For example, with usual atrial arrangement, if the atrioventricular connection is discordant, then the ventriculo-arterial connection is almost always discordant or double outlet right ventricle. The diagnosis requires the accurate recognition and description of ventricular morphology and ventricular topology, but the unifying feature will remain a common atrioventricular junction albeit with the right side of the common valve having a trileaflet structure instead of the left. Similar ventricular relationships may be encountered with atrial isomerism and atrioventricular septal defect in At the outset I explained that according to Anderson and Becker one of the hallmarks of an AVSD was absence of the atrioventricular septum. Yet they would accept that this will be absent in other situations such as tricuspid atresia, double inlet left ventricle with two atrioventricular valves and even some posterior ‘inlet’ perimembranous ventricular septal defects. These malformations, however, fail to satisfy a second criterion for inclusion, a common atrioventricular junction. But there is a close cousin, which, although characterised by absence of the atrioventricular septum and a common atrioventricular junction, is not necessarily an atrioventricular septal defect. In some cases of double inlet ventricle, a common atrioventricular valve neither straddles nor overrides the ventricular septum and is committed entirely to one ventricle. Such hearts are not examples, therefore, of an atrioventricular septal defect with ventricular imbalance but clear examples of a univentricular atrioventricular connection with double inlet. Even those who might argue the case for using the term unbalanced AVSD when there is a dominant left or right ventricle could not continue the argument in the presence of double inlet connection to a solitary indeterminate ventricle. It is, however, morphologically correct to describe the connection as double inlet when 75% or more of the common atrioventricular valve is committed to one ventricle in the presence of a second hypoplastic and rudimentary contralateral ventricular chamber . I recalFinally, I will put forth the question, ‘What is in a name, particularly when today’s imaging techniques show everything’? The fundamental reason for allocating names to congenital heart malformations is to allow communication between those working in the field. Names are also essential to research and audit. Surgeons must be able to investigate the results of radical repair of hearts with the various morphological features of an atrioventricular septal defect and identify any incremental risk factors for poor outcome. Retrospective review can only be made possible by an adequate system of nomenclature and classification.Learning to be a paediatric cardiologist or cardiac surgeon is extremely complex. For example, to the less experienced, echocardiographic, angiographic, CT or resonance images of the heart appear at first as a meaningless blur. Gradually, however, our brains are able to connect together the findings on clinical examination of the patient with the images that we see. For example, even without allocating a name, an echocardiographic four chamber section from a patient with a primum atrial septal defect will immediately trigger a variety of complex thoughts ranging from expectations of clinical findings, symptoms, natural history and likely outcome of repair. The surgeon will imagine the appearance of the heart in the operating room while the morphologist will be aware of what the heart would be like held in the hand and examined in the laboratory. For the individual expert, names have potentially become irrelevant. For those of us involved in managing patients with congenital heart disease it is often unwise to rely entirely on individual names for particular conditions because of the presence of unusual features or associated anomalies.Consider the hypothetical situation of a paediatric cardiologist who, on the basis of a cross-sectional echocardiogram, informs a cardiac surgeon about a patient with a primum atrial septal defect that requires routine repair, and the surgeon takes the patient to the operating room without carefully reviewing and discussing any investigations. For a simple primum defect, no doubt the outcome would be very good because, simply on the basis of the name, the surgeon would anticipate correctly the operative findings. But just imagine the likely consequence if in addition to the primum defect there had been double outlet right atrium, a small and restrictive primum defect with left atrial hypertension, double orifice left atrioventricular valve and left ventricular outflow tract obstruction  caused bConsider also another hypothetical situation of a four-month-old infant with isolated primum defect, mild to moderate left atrioventricular valve regurgitation with unexpected congestive heart failure and failure to thrive. The cardiologist was unable to be present when the case was shown to colleagues and surgeons, and an echocardiogram was interpreted as a straightforward ‘partial AVSD’ requiring early surgical repair and the management was agreed upon quickly. At operation the surgeons found an atypical left atrioventricular valve and could not achieve a complete operation. In a retrospective review, the outpatient report from the referring cardiologist was discovered.‘Partial Atrioventricular Septal Defect (Isolated primum ASD)Bileaflet left atrioventricular—deficient left mural leafletParachute deformity of left AV valveSmall/potentially stenotic left-sided valve orificeShort chords of left-sided valve orifice’This is an example of a case where access to the complete diagnosis at the multidisciplinary team meeting and a more careful review of the clinical history and the echocardiogram at the time would have alerted everyone to potential difficulties and possibly changed the clinical management and surgical approach and timing.Given the precision and quality of cardiovascular imaging now available and the ability to transmit digital images with great speed virtually anywhere, it is difficult to avoid the conclusion that names are less important than they were. We must not forget, however, that words, names and language are the essential prerequisites of communication, audit and teaching. Good practice in the management of congenital heart disease cannot be achieved without accurate communication! A complete and accurate description in the diagnosis will also alert the surgeon to potential difficulties that will be encountered during surgery, and, as I have tried to convey, there can be a complex constellation of deviations from the usual morphology. Indeed, I have also attempted to emphasise both the clinical  and scientific importance of preciseness. Preciseness, no matter how impractical it may be in contemporary ‘fast-track’ life and medicine, implies a deep understanding, which is a hallmark of the Anderson and Becker school of morphology. The marvellous contribution of Bob Anderson and his many collaborators to the understanding of congenital heart malformations has in part been made possible by the emphasis on nomenclature and precise communication. However, it is regrettable that his message seems not yet to have reached everyone.


Patients with pre-capillary pulmonary hypertension (PH) show poor survival, often related to right ventricular (RV) dysfunction. In this study, we assessed the 5-year prognostic value of a novel echocardiographic measure that examines RV function through the temporal relation between RV strain (ϵ) and area (i.e. RV ϵ-area loop) for all-cause mortality in PH patients.P < 0.05) at baseline. Univariate cox-regression analyses identified early systolic slope, systolic slope, peak ϵ, early diastolic uncoupling, and early/late diastolic slope to predict all-cause mortality , whilst peak ϵ possessed independent prognostic value (P < 0.05). High RV loop-score  showed poorer survival compared to low RV loop-score (Kaplan–Meier: P < 0.01). RV loop-score improved risk stratification in high-risk patients when added to established predictors.Echocardiographic assessments were performed in 143 PH patients (confirmed by right heart catheterization). Transthoracic echocardiography was utilized to assess RV ϵ-area loop. Using receiver operating characteristic curve-derived cut-off values, we stratified patients in low- vs. high-risk groups for all-cause mortality. Kaplan–Meier survival curves and uni-/multivariable cox-regression models were used to assess RV ϵ-area loop’s prognostic value . During follow-up 45 (31%) patients died, who demonstrated lower systolic slope, peak ϵ, and late diastolic slope  echocardiography assessment of PH patients. Pulmonary hypertension (PH) is a progressive pulmonary vascular disease, which is associated with a poor 5-year survival rate.Although right heart echocardiography is advised in suspicion of PH and/or during follow-up of patients with PH, it possesses inferior prognostic value compared to other clinical measures  and RHC.,Recently, we introduced the RV ϵ-area loop, which reflects the change of RV longitudinal ϵ across the cardiac cycle and is linked to the change in RV area.The primary aim of this study was to examine the prognostic value of characteristics of the RV ϵ-area loop for future all-cause mortality in patients with pre-capillary PH across a 5-year follow-up. We hypothesize that characteristics of the RV ϵ-area loop (e.g. slope of the systolic ϵ-area relation) possesses predictive value for all-cause mortality in patients with pre-capillary PH, independent from currently known predictors .Ethics approval was obtained from the Radboud University Medical Center ethics committee to perform the proposed work (reference number 2015-1832). This study was registered at the Netherlands Trial Register (NTR5230) and conforms to the standards set by the latest revision of the Declaration of Helsinki.Table 1.We included 177 patients with pre-capillary PH, confirmed by RHC, who underwent transthoracic echocardiography at the Department of Cardiology of the Radboud University Medical Center (Nijmegen) between June 2003 and June 2017. Patients with multifactorial PH were included when pre-capillary PH was confirmed and PH-modifying therapy was prescribed. Due to inadequate 2D image quality for RV longitudinal ϵ analysis, 44 patients were excluded, resulting in a final cohort of 143 patients. Additional information regarding the included population can be found in To address our aims, we retrospectively collected data on patient characteristics, PH-modifying therapy, 6M-WD and NT-proBNP at the time of echocardiographic assessment. Survival status of patients was retrieved from the Dutch population register at 21 January 2019, resulting in median follow-up of 60 (interquartile range 45–60) months while 91 patients fulfilled the maximal follow-up of 5 years.Echocardiographic data were obtained by experienced sonographers using ultrasounds machines of the Vivid series . Data were stored in raw DICOM format in a password-protected archive of the Department of Cardiology of the Radboud University Medical Center. Data were retrieved for subsequent analysis by a single experienced researcher using commercially available software . This researcher was blinded for the outcome during follow-up.Conventional echocardiographic indices were obtained in accordance with ASE Guidelines for echocardiographic assessment of the right heart.A modified apical four-chamber view, with a frame-rate of at least 40 frames per second, was used to assess simultaneous RV longitudinal ϵ and area. Images were optimized to ensure adequate endocardial delineation using gain, compression and reject. A region of interest (ROI) was drawn from the basal free to the basal septal wall enclosing the entire myocardium. Automatic analysis divided this ROI in six segments, the average of these segments  was used in subsequent analysis.Temporal RV longitudinal ϵ values were exported to a spreadsheet . To correct for differences in hazard ratio (HR) between subjects and length of the systolic and diastolic part of cardiac cycle, the temporal RV longitudinal ϵ values were divided in 300 points for systole and 300 points for diastole by cubic spline interpolation. For both systole and diastole, the 300 ϵ values were then split into 5% increments of the cardiac cycle providing 10 points in systole and 10 points in diastole. Concomitant time points, derived by tracing the echocardiography derived electrocardiogram signal, of the ɛ values were used in the same image and cardiac cycle to trace RV monoplane areas. For each patient, an RV ɛ-area loop was created.Figure 1. Based on our extensive pilot work,,,n = 7), with exception of UNCOUP_LD, we retrieved good to excellent ICC (Table S1).The RV ɛ-area loops were assessed by (i) the early systolic ɛ-area relation (ESslope), (ii) linear slope of ϵ-area relation during systole (Sslope), (iii) end-systolic peak ϵ (peak ϵ), (iv) diastolic uncoupling (i.e. mean difference between systolic vs. diastolic ϵ contribution to area change) during early filling (UNCOUP_ED), (v) diastolic uncoupling during late diastole (UNCOUP_LD), (vi) diastolic uncoupling during the entire cardiac cycle (UNCOUP), (vii) the early diastolic ɛ-area relation (EDslope), and (viii) the late diastolic ɛ-area relation (LDslope) as presented in Continuous variables were expressed as mean ± standard deviation in case of normal distribution. Normality of data distribution was examined using a Kolmogorov–Smirnov test. In case of non-Gaussian distribution, log-transformation was applied and data were presented as median (interquartile range). Categorical variables were expressed as percentage. Patients lost to follow-up were censored at the time of last available follow-up.Table S2). Based on this cut-off value, patients were divided into low vs. high risk for all-cause mortality. Cut-off values for established predictors  for low vs. high-risk group were based on current guidelines.Based on the optimal combination of sensitivity and specificity, derived from receiver operating characteristic curve (ROC) analyses at 5-year follow-up, cut-off values for all echocardiographic derived parameters were obtained , combining the risk stratifications of the individual characteristics. The RV loop-score was ranged between 0 and 6 (i.e. 1 point for each characteristic in the high-risk category), categorizing patients with ‘low score’ (RV loop-score of 0–3) vs. ‘high score’ (RV loop-score of 4–6). First, we examined the Kaplan–Meier curve based on the RV loop-score. Secondly, we examined if the RV loop-score improved risk stratification based on the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for diagnosis and treatment of PH  that is clinically used to categorize PH patients into low, intermediate and high risk.Kaplan–Meier survival curves were constructed to assess discriminative capacity of the RV ϵ-area loop characteristics. Univariate cox proportional HRs were determined to assess the predictive value of RV ϵ-area loop characteristics for all-cause mortality. Subsequently, significant univariate predictors were fitted into multivariable models to determine their independent predictive value compared to the reference model . Finally, we calculated a combined RV loop-score based on the RV ϵ-area loop characteristics with predictive value after univariate cox regression analyses  pulmonary artery hypertension and 22 with multifactorial PH. The remaining 26 patients were diagnosed with WHO class IV PH, i.e. chronic trombo-embolic PH.P < 0.05, Table 2). A marked rightward shift in the RV ϵ-area loop was visible at baseline between surviving and deceased patients . A significantly lower Sslope, EDslope, and peak ϵ was found in deceased vs. surviving patients after 5-year follow-up . Kaplan–Meier survival analysis revealed significant differences in survival when patients were categorized based on ESslope, Sslope, Peak ϵ, EDslope, and LDslope of the RV ϵ-area loop .After a median follow-up period of 60 (45–60) months, 45 out of 143 patients died . Patients who died were older, predominantly male sex, had a higher NT-proBNP level, showed larger RVEDA and RVESA, and lower 6M-WD and RVFAC at baseline . Multivariable models revealed that RVESA (>16.9 cm2), RVFAC (<25.55%), and peak ϵ (>−14.45%) remained significant predictors when added to the reference model (Table 4).Univariate cox regression analysis revealed age, sex, NT-proBNP, 6M-WD, RVEDA, RVESA, RVFAC, TAPSE, and RV ϵ-area loop characteristics  as univariate predictors for 5-year all-cause mortality . HR showed a 3.182 (1.768–5.726) times higher risk for all-cause mortality in those with a ‘high’ RV loop-score compared to ‘low’ loop-score. More importantly, the RV loop-score improved risk classification following the 2015 ESC/ERS guidelines , with high-risk individuals with ‘low’ RV loop-scores showing significantly better survival than high-risk patients with an ‘high’ RV loop-score . The RV loop-score did not significantly improve classification of patients at low (P = 0.83) and intermediate (P = 0.91) risk.Kaplan–Meier survival curves revealed significant differences in 5-year survival between ‘low’ and ‘high’ RV loop-scores  A markedly different RV ϵ-area loop is present in PH patients who died across 5-year follow-up compared to surviving patients, (ii) RV ϵ-area loop characteristics show significant prognostic value for 5-year all-cause mortality in PH patients, with RV longitudinal peak ϵ possessing independent prognostic value, (iii) the RV loop-score, i.e. reflecting the number of ‘abnormal’ loop characteristics, successfully predicts 5-year all-cause mortality in PH patients but also improves risk stratification in the high-risk population. Taken together, our findings suggest the RV ϵ-area loop predicts all-cause mortality in patients with pre-capillary PH and may reclassify some patients from the high-risk group to an intermediate-risk group. The non-invasive nature and relative simplicity of measuring the RV ϵ-area loop, support the potential clinical relevance of echocardiography for (repeated) assessment of PH patients.2 change in area in the deceased patients compared to those who survived. These adaptations may be the consequence of the RV being exposed to increased afterload.The marked shift between the RV ϵ-area loop of the surviving and deceased patients suggests the presence of a (further) impairment in RV function at the time of echocardiographic assessment in the deceased patients. The lower peak ϵ and flatter systolic ϵ-area slopes may be related to an impaired RV systolic function, presented by the smaller deformation (i.e. ϵ) of the ventricular wall for each cmTable 4). These results confirm findings of previous studies assessing the prognostic value of echocardiography in patients with pre-capillary PH.,Despite the growing consensus of the importance of RV function in patients with pre-capillary PH,r2 = 0.07–0.45) between indices of systolic function  and diastolic function  of the RV ϵ-area loop. This data highlights that the combined temporal data on the relative contribution of strain to area change during both systole and diastole, and the association between systolic and diastolic function, provide in depth insights in ventricular function compared to single peak value-based assessments such and peak strain or RVFAC. The dynamic temporal data acquired within the strain-area loop therefore increases its predictive value over functional measures at a single point during the cardiac cycle.A key observation in our study was the prognostic value of both systolic and diastolic RV ϵ-area loop characteristics. Traditionally, markers of RV function only include RV systolic function. In a recent study, it was demonstrated that deterioration of RV diastolic function may precede deterioration of RV systolic function in patients with pre-capillary PH.r2 = 0.001–0.47), support the potential value of calculating a multi-parameter value such as an RV loop-score. Whilst the RV loop-score showed strong and significant prognostic value, adding the RV loop-score to the clinically used, 2015 ESC/ERS guidelines improved risk stratification for the high-risk population. More specifically, high-risk patients with a low RV loop-score showed a significantly better 5-year survival than those with a high RV loop-score. Effectively, the high-risk patients with low RV loop-scores were reclassified as moderate risk, given their similar survival curves . This may be explained by the absence of echocardiographic RV function indices in the 2015 ESC/ERS risk stratification guidelines. Since deterioration of RV function remains the main cause of death in patients with pre-capillary PH,Presence of predictive value of the individual indices (including both systolic and diastolic RV function), and absence of strong relations amongst the six individual RV ϵ-area loop characteristics pharmaceutical therapy. Specifically, excessive physical activity is not recommended in high-risk patients, whilst an increasing amount of follow-up visits and more aggressive PH-modifying therapy strategy is advised for high-risk patients. Successfully reclassifying the high-risk to intermediate-risk, i.e. 51% of our population, will therefore impact treatment (and lower associated costs and risks for complications/side-effects). Finally, the ability for repeated assessment of RV function enables evaluation of disease progress and efficacy of (non)pharmaceutical therapy.n = 54) received PH-modifying therapy prior to inclusion. A sub-analysis revealed no differences in the RV ϵ-area loop characteristic at the time of inclusion between those with and without PH-modifying therapy prior to inclusion (Table S3). Moreover, patients with PH-modifying therapy at time of inclusion, typically started this within weeks prior to inclusion, whilst the majority started PH-modifying therapy within 1 week after the day of inclusion. Therefore, this short time-frame wherein all participants started PH-modifying therapy unlikely affected the main outcomes of our study. Finally, the current method to assess the ɛ-volume loops and their characteristics is currently only partially automated and thus time-consuming. Automated self-learning analysis protocols should be created prior to clinical implementation. In response to the time-consuming nature of the current loops analysis we have analysed a simplified parameter, here called the end-systolic-end-diastolic ϵ-area slope (ESEDslope), which provides the systolic slope based on individual measures of just RVEDA, RVESA, and Peak ɛ. Similar to the Sslope significant differences were found for ESEDslope between groups  and a significant HR  using a univariate analysis. In line with the Sslope significance disappeared when ESEDslope was added to the reference model . This suggests that the combination of characteristics for the loop may outperform individual, simplified measures. This outcome supports the use of multiple measures from the ϵ-area loop in predictive analysis.Although all patients had pre-capillary PH, different aetiology was present. Whilst our sample size is sufficiently powered to identify predictors for all-cause mortality in PH, it does not allow for sub-analyses related to the various aetiology of PH. Another limitation is that some patients  risk assessment model. These results support the clinical potential of echocardiography-based assessment of the RV ϵ-area loop for risk stratification and survival-analyses in patients with pre-capillary PH. Future studies are warranted to further explore its potential use, especially in the context of repeated assessment of echocardiography to monitor progression and adjust treatment to optimize care for this vulnerable group of patients.European Heart Journal - Cardiovascular Imaging online.The data underlying this article will be shared on reasonable request to the corresponding author.This study was supported by a junior researcher grant from the Radboud Institute for Health Sciences.Conflict of interest: A.P.v.D. reports grants and personal fees from Actelion, outside the submitted work. All other authors reported nothing to disclose.jeaa143_Supplementary_DataClick here for additional data file.


Myocardial atrophy with fibrosis and fatty infiltration involving the cardiac conduction system is relatively unusual in horses. We herein report of such a case in a 13‐year‐old Arabian broodmare that had spontaneously died on a paddock. An autopsy revealed multifocal myocardial atrophy with concomitant fibrosis and fatty infiltration in both the ventricles and interventricular septum. The Purkinje fibres in the ventricles and interventricular septum were surrounded by thick fibrous or adipose tissues adjacent to atrophic myocardial cells. Myocardial fibrosis and fatty infiltration were likely secondary to myocardial atrophy, occurring as a pathological response triggered by the repair of muscular wall injury. However, there were no major vascular pathologies (e.g. atherosclerosis and arteriosclerosis); hence, the pathogenesis of myocardial atrophy was unclear. There was no evidence of myocardial atrophy - induced pathologies such as infarct, ischaemic lesions, myocardial degeneration, myocarditis and endocarditis. However, such an unusual histopathological pattern may be associated with rapid clinical deterioration and death. Idiopathic multifocal myocardial atrophy. Most recent studies on cardiac pathologies have focused on racehorses, with special attention to sudden death or arrhythmias  before death detected a cardiac arrhythmia consistent with ventricular bigeminy. Three months before the incident, an endometrial biopsy and cytology of the uterine lavage fluid was performed. Results of a histopathological examination of the uterus corresponded to Grade 1, per the classification system proposed by Kenny & Doig ; no path33.1An autopsy was performed approximately 5 hr after death. Results of an external examination indicated a high degree of obesity; the subcutaneous and retroperitoneal tissues held large deposits of yellow fat. The atria and ventricles were dilated and filled with abundant dark‐red, poorly coagulated blood clots, and abundant fatty tissues were present outside the pericardial and epicardial surfaces in the right and left ventricles around the coronary blood vessels. The ventricles had conspicuous, sharply demarcated, unencapsulated, streaky, light greyish‐white lesions that varied in size but were generally massive, measuring 0.5– 8.0 x 1.0–15. 0 cm. They were isolated, regional  or a coalescence of multiple lesions that were primarily located in the muscular layers of the right and left ventricular free walls Figure . HoweverStrongylus vulgaris), in the intima of the aorta. However, there were gross changes in organs other than the heart, such as diffuse, mild to moderate pulmonary congestion; atelectasis; and congestion in the major internal organs and pia matter of the cerebrum and cerebellum.In the interventricular septum, the lesions were distributed from the apex  to the middle portion of the heart . In the right and left ventricular free walls, the lesions were distributed from the inferior to the middle portion of the ventricular free walls, including the walls of the coronary artery. No gross lesions were found in the apex, atria, sinoatrial nodal region or atrioventricular nodal region. We did not observe other gross cardiac lesions, such as coronary aneurysm, medial degeneration of the aorta or extra‐pulmonary artery, or nodular fibrous plaques (associated with the migrating larvae of 3.2µm - thick sample slices that had been stained with either Masson ʼ s trichrome or haematoxylin and eosin.Based on a protocol developed by Diab et al. , tissue The macroscopically observed greyish‐white lesions of the ventricles were histologically correlated to myocardial atrophy with concomitant interstitial fibrosis and infiltration of adipose tissues, around the bundle of His Figures , 4. The 4The cardiac lesions in the present case were histologically characterized by multifocal myocardial atrophy with concomitant fatty infiltration and myocardial fibrosis between cardiomuscular fibres/bundles, and nests of Purkinje fibres that were sequestered primarily by prominent fibrous connective tissues or adipose tissues in the interventricular septum and the free walls of both ventricles.In animals, the atrophy of cardiac myocytes develops secondarily to conditions such as cachexia, myocarditis, ischaemia due to coronary arteriosclerosis, tumour compression, muscular dystrophy or hereditary loss of cardiomyocytes (Agudelo, Svoboda, Husnik, & Dvir, Myocardial fibrosis has been reported in old horses above 12 years in association with areas of myocardial degeneration and arteriosclerotic changes (Marcus & Ross, Cases similar to ours have been reported, in which nonathletic horses suffered cardiac fatty changes (Baker & Kreeger, The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.Midori Goto Asakawa and Masa‐aki Oikawa: Conceptualization; Formal analysis; Investigation; Validation; Writing‐original draft; Writing‐review & editing. Wasiq Mehmood: Formal analysis; Investigation; Methodology; Validation; Writing‐review & editing. Mohammed Ali: Conceptualization; Investigation; Project administration; Resources; Supervision; Validation; Writing‐review & editing.The authors confirm that the ethical policies of the journal. As noted on the journal`s author guidelines page, have been adhered to. No ethical approval was required as this is an investigation of an animal at post‐mortem examination.https://publons.com/publon/10.1002/vms3.350.The peer review history for this article is available at


Rapid and accurate identification of right ventricular (RV) dysfunction is essential for decreasing mortality associated with acute pulmonary embolism (PE), particularly for non-high-risk patients without hypotension on admission. This study aimed to develop a rapid and accurate tool for predicting the risk of RV dysfunction in non-high-risk patients with acute PE.The medical records of non-high-risk patients with acute PE admitted to Shengjing Hospital of China Medical University between January 2011 and May 2020 were retrospectively analysed. The primary outcome of this study was RV dysfunction within 24 h after admission. The enrolled patients were randomized into training or validation sets as a ratio of 2:1. In the training set, a nomogram was developed, and the consistency was corroborated in the validation set. The areas under the receiver operating characteristic curves (AUCs) and 95% confidence intervals (CIs) were calculated.p < 0.001) and 0.839 in the validation set . The predictive tool was published as a web-based calculato (https://gaoyzcmu.shinyapps.io/APERVD/).A total of 845 patients were enrolled, including 420 men and 425 women with an average age of 60.05 ± 15.43 years. Right ventricular dysfunction was identified in 240 patients (28.40%). The nomogram for RV dysfunction included N-terminal pro-brain natriuretic peptide, cardiac troponin I, and ventricular diameter ratios, which provided AUC values of 0.881 in the training dataset : 0.868–0.898, The combination of CT and laboratory parameters forms a predictive tool that may facilitate the identification of RV dysfunction in non-high-risk patients with acute PE. Patients suffering from acute pulmonary embolism (PE) have a wide range of short-term prognoses . High-riIn acute PE, the standard diagnostic method for RV dysfunction is echocardiography; however, an experienced sonographer is not always available . The assAlthough some methods for predicting RV dysfunction have been applied in the clinical setting using laboratory and computed tomography (CT) parameters, their utilization and predictive values remain controversial , 8–10. IThis was a retrospective study in Shengjing Hospital of China Medical University from January 2011 to May 2020.The non-high-risk acute PE patients who were diagnosed by CT pulmonary angiography (CTPA) and more than 18 years were selected preliminarily on admission into our hospital. The definition of non-high-risk acute PE patients was referred to 2019 European Society of Cardiology guidelines for acute PE [The demographic characteristics and baseline data were collected. The systolic pressure, heart rate and arterial oxyhemoglobin saturation were obtained on admission records together with a detailed medical history. Serum c-Tn I and NT-pro BNP were measured within 2 h followed by a diagnostic CTPA in patients or by diagnosis of the diseases when patients with severe symptoms including dyspnoea, chest pain, haemoptysis, and other related symptoms on admission. The c-Tn I and NT-pro BNP data were collected.A 64-deector-row CT was used to perform the pulmonary arteriography the details of the equipment was listed as follow: KV-120; Toshiba Medical Systems Corporation, Tokyo, Japan; The acquisition parameter was listed as 1.0 mm sections with 370 mA and 120 kV. Approximate 100 mL contrast of iodized non-ionic type was injected into elbow vein by an automatic dual-tube high-pressure injector from the thoracic inlet to the upper abdomen at a rate of 4 ml/s.In consideration of suitability for clinical practice, the items of CTPA parameters were reconstructed. Clot location was defined as three types: Saddle-main pulmonary artery (MPA) embolism, MPA embolism and non-MPA embolism. MPA was extracted from CTPA data firstly from the inlet of pulmonary artery trunk to the outlet of right and left side MPA . If throThe primary endpoint of this study was defined as occurring RV dysfunction within 24 h of admission by an echocardiography by an IE Elite ultrasound machine (Philips) equipped with an transducer (frequency conversion 1–5 MHz). Occurrence of anyone or more appearances was defined as RV dysfunction: RV diameter > 30 mm from 4-chamber or parasternal view. At end-systole. RV/LV 4-chamber diameter ratio > 0.9 RV hypokinesia occurred at free wall. The jet of tricuspid regurgitation’s velocity increased at apical 4-chamber view , 16. AllThe enrolled patients were randomized into a training set and a validation set as a ratio of 2:1.The training set was used to develop a nomogram for predicting RV dysfunction as the standard of Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) standard . The bioIn this study, continuous data is expressed as mean ± standard deviation and tested with a Student’s t test. The categorical data is expressed as number (%) and compared with a Chi-square test. CART analysis was used to dichotomize each parameter and identify significant parameter , 20.p < 0.05 and all analyses were performed using R software .To evaluate the correlation to RV dysfunction, univariate and multivariate logistic regression analysis were performed. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from the logistic regression analysis. The nomogram for predicting RV dysfunction was created by regression coefficient of each variable based on the multivariate logistic regression above. The variable with the highest weight was defined as the range from 0 to 100 points. The other variable scores was calculated based on this variable with the highest weight. Each variable ranged from 0 to 100 points. The scores of each variable were added into total scores. . By the p < 0.001) than patients without RV dysfunction. Patients with RV dysfunction were also more likely to have MPA embolisms and saddle-MPA embolisms and less likely to have non-MPA embolisms than patients without RV dysfunction . Furthermore, patients with RV dysfunction had a significantly greater mean RV short-axis diameter, RV 4-chamber diameter, RA 4-chamber diameter, RV/LV short-axis diameter ratio, RV/LV 4-chamber diameter ratio, and RA/LA 4-chamber diameter ratio  than patients without RV dysfunction. However, patients with RV dysfunction had significantly lower mean values of LV short-axis diameter, LV 4-chamber diameter, and LA 4-chamber diameter than patients without RV dysfunction  . In addition, 53 patients were identified as having a pre-existing heart disease, including 24 patients with definitive heart failure, 21 patients with cor pulmonale, and 8 patients with coronary artery disease. RV dysfunction was diagnosed in 240 patients  according to the echocardiography results. A total of 605 patients  were not found to have RV dysfunction. The patients with RV dysfunction had significantly higher heart rate, c-Tn I, and NT-pro BNP , c-Tn I , RV/LV short-axis diameter ratio , and RV/LV 4-chamber diameter ratio  each independently predicted RV dysfunction (Table Four variables were considered significant predictors of RV dysfunction and were dichotomized: NT-pro BNP (≥ 650 pg/mL vs. < 650 pg/mL), c-Tn I (≥ 0.055 μg/L vs. < 0.055 μg/L), RV/LV short-axis diameter ratio (≥ 1.00 vs. < 1.00), and RV/LV 4-chamber diameter ratio (≥ 0.93 vs. < 0.93). A multivariate logistic regression analysis using the training dataset revealed that NT-pro BNP  and in the validation set  Fig. . The calhttps://gaoyzcmu.shinyapps.io/APERVD/) that assigned patients to a high-risk (≥ 92 points) or low-risk group (< 92 points) .Additional file 2. Measurement of cardiac diameter (CTPA images describing the methods used to measure the heart dimensions used in this study).Additional file 3. Web-based calculator for predicting RV dysfunction .


Ex vivo experiments were performed on excised formalin-fixed hearts of aged SHRs (n = 4) and age-matched controls (n = 4). The DT-MRI-derived fractional anisotropy (FA), longitudinal diffusivity (λL), transversal diffusivity (λT), and mean diffusivity (MD) served as the readout parameters investigated at three transmural zones . The helix angles (HAs) of the aggregated cardiomyocytes and the orientation of laminar sheetlets were also studied. Compared with controls, the SHRs exhibited decreased epicardial FA, while FA changes in the other two transmural regions were insignificant. No substantial differences were observed in the diffusivity parameters and the transmural course of HAs between the two groups. A consistent distribution pattern of laminar sheetlet orientation was not identified for either group. Our findings are in line with the known cellular microstructure from early painstaking histological studies. Biophysical explanations of the study outcomes are provided. In conclusion, our experimental findings indicate that the epicardial microstructure is more vulnerable to high blood pressure leading to more pronounced changes in this region during remodeling. DT-MRI is well-suited for elucidating these alterations. The revealed transmural nonuniformity of myocardial reorganization may shed light on the mechanisms of the microstructure-function relationship in hypertension progression. Our results provide insights into the management of patients with systemic arterial hypertension, thus prevent the progression toward heart failure. The findings of this study should be acknowledged by electromechanical models of the heart that simulate the specific cardiac pathology.The long-standing high blood pressure  overworks the heart. Microstructural remodeling is a key factor of hypertensive heart disease progression. Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful tool for the rapid noninvasive nondestructive delineation of the cardiomyocyte organization. The spontaneously hypertensive rat (SHR) is a well-established model of genetic hypertension. The goal of this study was to employ high-resolution DT-MRI and the SHR animal model to assess the transmural layer-specific remodeling of myocardial microstructure associated with hypertension.  Elevated blood pressure in the arteries  is a serious condition that can lead to heart failure, stroke, kidney failure, and blindness among othersFocussing on the heart, the chronic elevated arterial pressure adversely affects the cardiac function by compromising the organ's ability to work as a pump which escalates into heart failure. But a key determinant of the heart's pumping function is its unique three-dimensional (3D) microstructural organization  has emerged  that served as the controls. SHR . EF was measured using the clinical cardiac software Myovation designed for the Xeleris workstation .Under deep isoflurane-inhalation anesthesia, each intact heart was rapidly removed from the chest and flushed with warmed isotonic saline. Once the heart was rinsed, it was weighed and instantaneously placed in 60cc of 10% buffered formalin  to induce tissue fixation at a contraction state. All hearts of this study were approximately in the same state of contraction as confirmed by measurements of the mean ventricular wall thickness  coil  was used for signal transmission and reception.Whole heart imaging was carried out at the Small Animal MRI Imaging Facility of the University of Utah using a 7T horizontal bore MRI scanner  interfaced with the Paravision 5.1 software package. All MRI acquisitions were performed at typical room temperature, approximately 20°C. For imaging, each heart was placed in a sealed 5-mL standard syringe filled with Fomblin  to increase contrast and eliminate susceptibility artifacts near the boundaries of the myocardium. Hearts were secured inside the containers using gauze to prevent the specimen from floating in the container. The long axis of each heart was aligned with the G) = 30 G/cm, resulting in a nominal b value of 1,000 s/mm2, accounting for all imaging gradients and cross-terms between imaging and diffusion gradients. The diffusion-induced signal decay was measured along 12 optimized  = 19.224 ms, pulse repetition time (TR) = 500 ms. Diffusion encoding was carried out using a pair of trapezoidal gradient pulses with parameters: gradient duration (δ) = 4 ms, inter-gradient separation (Δ) = 10 ms, rise time = 0.25 ms, maximum strength of the gradient pulse , multiplied by the factor 0.655Five short-axis slices, evenly-spaced between the left ventricular base and apex, were analyzed for each heart. Endocardial and epicardial contours were semi-automatically acquired in the B0 images using cubic splines de Boor, . Extra cd1, d2, d3 (where d1 ≥ d2 ≥ d3), and the corresponding eigenvectors e1, e2, e3. The eigenvectors represent the three principal axes of diffusion, whereas each eigenvalue is equal to the rate of diffusion along the direction that the paired eigenvector points. Therefore, any voxel, at which the diffusion tensor diagonalisation resulted in at least one negative eigenvalue, was excluded on thermodynamic grounds. The longitudinal diffusivity (λL), transversal diffusivity (λT), mean diffusivity (MD) and fractional anisotropy (FA) were subsequently derived from the three eigenvalues using the following formulae, respectively:L represents the water diffusivity parallel to the long axes of cardiomyocytes, while λT corresponds to water diffusivity perpendicular to the axonal myocardial cells. λL is considered to represent cell axonal integrity, whereas λT is regarded as a measure of cell integrity along its diameter (myelin integrity). To quantitatively compare the differences in the above parameters between the two groups, the mean values were computed for each of the three transmural zones across the five short-axis slices.The rank two symmetric diffusion tensors were estimated on a pixel-by-pixel basis over the myocardial tissue region using the diffusion signal attenuation data, the reference data, and a custom-made multi-variate nonlinear least-squares curve fitting algorithm  maps were determined, where HA is defined .p = 0.0286), confirming the development of left ventricular hypertrophy in the SHRs at the time of our experiments. The mean SNR for the B0 images was approximately 90 in both groups. The average EF was 69% for the WKYs and 50% for the SHRs, confirming that the SHRs were in borderline heart failure stage.The average heart-to-body weight ratio was 0.6550% for the SHRs vs. 0.3450% for the WKYs (p = 0.0286), when compared to controls  between the degree of cardiac hypertrophy and epicardial FA. A summary of the quantitative comparison results with respect to the degree of anisotropy and magnitude of water diffusion is presented in Hypertension gave rise to a statistically significant decrease in epicardial FA   was preserved after hypertension . By runn 0.9829) . Finally 0.9829) .Unrelenting high blood pressure brings the left ventricle to a pathological pressure overload state which, when left uncontrolled, mediates cardiac remodeling and dysfunction  at various depths across the left ventricular wall in order to fully understand and characterize the behavior of the whole organ in hypertension.The fact that the imaging experiments of this investigation were performed when the SHRs were at the early systolic failure stage of the hypertensive heart disease hints that our findings could also be used to help identify those patients for whom it is required to adopt therapeutic strategies that prevent the progresion toward heart failure. Examples of such treatment might be the blunting of intracellular apoptotic pathways and the stimulation of cellular survival mechanisms that slow down the cell death processes .The datasets generated for this study can be found in figshare repository (The animal study was reviewed and approved by Animal Welfare Research Committee of Lawrence Berkeley National Laboratory.GG conceived and designed the study, and wrote the paper. AG analyzed the data, wrote the software used in analyses, and wrote the paper. All authors agree to be accountable for the content of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Being woman is associated with higher survival rates after transcatheter aortic valve replacement (TAVR) despite the increase in periprocedural complications. The left ventricle (LV) remodelling process that follows TAVR is considered to play an important role. We aim to investigate whether gender difference affects the process of LV remodelling after TAVR.A total of 100 patients (50 men and 50 women) after TAVR were enrolled. Echocardiography was performed at baseline before the TAVR procedure and repeated upon discharge, and at three, nine and 12 months post‐TAVR.Women exhibited an early regression of LV mass and the LV mass index (LVMi) decreased 12.0% from 148.3 ± 48.0 to 130.5 ± 43.7 g/m2 at just a median of 17 days after the procedure (P < .001). Almost one‐half of the LVMi regression occurred by 17 days post‐TAVR and the LVMi regressed 22.0% by 12 months post‐TAVR. In contrast, the regression of LVMi in men seemed to be more gradual and the significant regression of LVMi from baseline began to be observed since three months later after TAVR. The LVMi reduction at nine months was 11.5% and achieved 15.4% over one year. Multivariable logistic regression analysis showed only the female sex, better LVEF and greater baseline LVMi were independently associated with greater LVMi regression after TAVR, indicating female gender is an independent predictor for favourable LV remodelling after TAVR.In conclusion, female patients with AS had favourable reverse remodelling with greater and earlier LV mass regression post‐TAVR compared with the male patients. The process of LV remodelling post‐TAVI likely contributes to the sex‐based differences in outcome after TAVI. The pressure overload in the LV caused by AS induces cardiac muscle hypertrophy and interstitial collagen deposition, leading to structural changes in the LV (ie LV remodelling). Sex appears to exert a strong influence on LV remodelling in surgical aortic valve replacement.22.12) were evaluated. All patients had New York Heart Association (NYHA) symptoms exceeding class II and were slated to undergo TAVR. These patients were selected for TAVR after a heart team discussion deemed them either unsuitable or too high‐risk for surgical aortic valve replacement. Their individual operative risk was calculated using the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) system. Patient selection was based on the approved indication for TAVR in Taiwan using either of the following criteria: (a) patients considered to be at high surgical risk with logistic EuroSCOREs ≥ 20%; (b) patients aged over 80 years old; (c) a history or the presence of previous cardiac surgery, porcelain aorta, thoracic burning sequelae contraindicating open heart surgery, mediastinum radiotherapy, severe connective tissue disease contraindicative to surgery, cirrhosis of the liver (child class A or B) or severe pulmonary insufficiency with forced expiratory volume in one second (FEV1) under one litre. The selection of patients for whom TAVR was determined to be the most suitable treatment approach required the clinical consensus of a multidisciplinary team comprised of cardiac surgeons, interventional cardiologists, anaesthetists and imaging specialists. The main exclusion criteria were a native aortic valve annulus of less than 18 mm or more than 29 mm, acute myocardial infarction for under 14 days, a left ventricular ejection fraction below 20%, active infection, hemodynamic instability or a life expectancy under 12 months. This study was approved by the institutional research board in Taipei Veterans General Hospital and followed STROBE statement and the broader EQUATOR guidelines.From May 2010 to March 2016, a total of 130 consecutive patients with severe, symptomatic AS  indefinitely and clopidogrel (75 mg/d) for three to six months following the procedure.2.3Echocardiography was performed using a GE Vivid E9 system  with a 4‐MHz transducer. An independent core laboratory analysed all of the patient echocardiograms. The mass of the LV was calculated using the formula put forth by the American Society of Echocardiography and indexed to body surface area (termed LV mass index).2.4The 30‐day combined safety endpoint is defined by the VARC‐2 [13] as a composite of all‐causes of mortality, major stroke, life‐threatening or disabling bleeding, acute stage 2 or 3 kidney injury including renal replacement therapy, major vascular complications and repeat procedure for valve‐related dysfunction. Stroke was defined as a focal neurologic deficit lasting over 24 hours or a focal neurologic deficit lasting under 24 hours with imaging findings of acute infarction or haemorrhage. The VARC‐2 proposed using the AKIN system for reporting acute kidney injury (AKI).2.5t test, which enabled evaluation of the differences at each LVMi follow‐up. A logistic regression analysis was performed to investigate the independent factors potentially contributing to LV remodelling after the TAVR procedure.Data were expressed as the mean ± standard deviation for the numeric variables and as a per cent for the categorical variables. Continuous variable comparisons between groups were achieved using a one‐way analysis of variance (ANOVA). Subgroup comparisons among the categorical variables were assessed using the Chi‐square and Fisher's exact tests. Serial changes in LV mass index (LVMi) post‐TAVR were analysed using a paired 3A total of 100 severe, symptomatic AS patients (n = 50 men and 50 women) received echocardiograms measured at baseline, discharge, and three and nine months post‐TAVR were enrolled in this study. Echocardiograms were not obtained post‐TAVR for 29 patients after one year for the following reasons: noncardiac‐related deaths (n = 13); cardiac‐related deaths (n = 8); underwent follow‐up at a referral hospital (n = 7) and poor image quality (n = 2). The study flow and baseline characteristics are listed in Table 2. The female subjects had higher EuroSCOREs  and shorter statures (151.3 ± 4.5 vs 164.5 ± 6.2 cm) and weighed less (56 ± 10.5 vs 65.3 ± 11.6 kg) than the men, though both groups had similar body mass indexes (BMIs). The prevalence of co‐morbidities including hypertension, diabetes, bicuspid aortic valve, history of CAD, previous coronary intervention, peripheral vascular disorder, atrial fibrillation, previous stroke and percentage of stage III‐VI congestive heart failure (CHF) were comparable for both sexes. Although there is a slightly higher percentage of low‐flow low gradient aortic stenosis (PLF‐LG AOST) in woman, their difference is insignificant . Echocardiographic analysis revealed narrower aortic roots  and smaller aortic valve areas in women , but indexed aortic valve area, mean pressure gradient, peak pressure gradient, ejection fraction, LV mass and indexed LV mass were similar in both sexes .The study population had a mean age of 80.21 ± 8.37 years and an average aortic valve area of 0.70 ± 0.23 cmThe procedural details are listed in Table 2  at only a median of 16.7 days after the procedure (P < .001). Significant LVMi regression was observed at the time of discharge in the female patients: the mean fractional LVMi regressed by 12.0% at 16.7 days after TAVR and achieved 22.0% after one year . The mean fractional decrease of the LVMi was 11.5% at the nine‐month follow‐up and reached 15.4% after one year . Table Table r Figure . In contr Figure , suggest4Our current result demonstrated that women had favourable reverse remodelling with significant LV mass regression occurring within the first two weeks after the procedure. In contrast, the regression of the LVMi in men seemed to be more gradual. The overall percentage of LVMi regression was greater among women. Additionally, the female sex, better LVEF and baseline LVMi were independently associated with greater early LV remodelling process, indicating that these could be used as indicators for early LV mass regression post‐TAVR in the Asian population.The pressure overload in the LV caused by AS induces cardiac muscle hypertrophy and interstitial collagen deposition, leading to structural changes in the LV (LV remodelling). LV remodelling alone can greatly impact morbidity in this patient population.Previous studies have suggested that female sex is associated with better mid‐ and long‐term survival post‐TAVR despite the increased rate of periprocedural complications.Cellular, molecular and neurohormonal mechanisms underlying the differential response of the sexes have been proposed and include increased interstitial fibrosis, greater activation of pro‐fibrotic and pro‐inflammatory pathways, and the differential expression of the androgen and oestrogen receptors, respectively.P < .001 for both) with similar patterns and incremental regressions; however, the overall percentage of LVMi regression was greater in women (P = .004). In contrast, Stangl et al found that the LVM and the LVM index had both decreased significantly at the three‐month post‐TAVR follow‐up without relevant differences between the sexes. Furthermore, although there is no difference in paradoxical low‐flow low gradient aortic stenosis (PLF‐LG AOST) percentage between genders, the female patients have higher baseline valvulo‐arterial impedance (Zva). The valvulo‐arterial impedance (Zva) provides an estimate of the global left ventricle (LV) hemodynamic load that results from the summation of the valvular and vascular loads.The present study provides additional insight into the timeline of LV mass regression after TAVR. It has been well documents in the literature that most of the mass regression occurs within 30 days post‐TAVI, at rates of 3%‐10%.4.1While our study did not use a matched‐control group design, the baseline risk factors, severity of the AS, included valve area, and pressure gradient were similar between the sexes. Second, most of the cases in this study used self‐expandable valves, but the percentage of balloon‐expendable valves and self‐expandable valves was nonsignificant difference in both groups. Third, in order to evaluate serial LVMi changes after TAVI, only these patients who received regular echocardiography at least nine months in the hospital were analysed in this study, the possible existence of selection bias cannot be excluded. Furthermore, some useful information such as global longitudinal strain by STE or mitral annulus displacement by MAPSE was not recorded in our current study. Finally, longer follow‐up periods will be useful for determining the long‐term impact of LVMi regression and any associated clinical outcomes of the TAVI procedure.5In conclusion, our current results demonstrated that female patients with AS had favourable reverse remodelling with greater and earlier LV mass regression relative to the males one. The favourable LV reverse remodelling observed in women might provide a mechanistic explanation for their survival advantage. Furthermore, better LVEF and higher baseline LVMi were associated with earlier LV remodelling post‐TAVR.There is no conflict of interest.


Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction.n = 23) or sham  surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed.Wistar rats were subjected to aorto-caval shunt  showed clinical signs of RV failure , whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGFβ1 and pSMAD2/3), or fibrosis were present at any time point.In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model. Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. When exposed to chronic abnormal loading conditions, as is often the case in patients with congenital heart disease, deterioration of RV function and progression toward failure can occur . AbnormaFibrosis is a process of excessive deposition of extracellular matrix that is observed in various types of heart failure, and is generally regarded as a detrimental factor and a potential treatment target in heart failure therapy . Indeed,n = 24) or sham surgery . The ACS was performed as described previously  were randomly subjected to aorto-caval shunt surgery , 3 months after surgery , and 6 months (6 m) after surgery . Prior to termination, echocardiography and invasive RV pressure–volume analysis was performed, as described below.Animals were sacrificed at three different time points: 1 month after surgery (ACS 3), as described previously  under inhalation of 2–3% isoflurane. Flow-measurements of the aorta and pulmonary artery were performed, and LV cardiac output (CO) and pulmonary artery acceleration time (PAAT) were calculated. In the apical four-chamber view, LV internal diastolic diameter (LVIDd), RV internal diastolic diameter (RVIDd), tricuspid annular plane systolic excursion , and the presence of regurgitation of the mitral valve or tricuspid valve were assessed. LV ejection fraction (EF) was assessed using M-mode in the short axis, using Teichholz’s formula. RVIDd, LVIDd, and TAPSE were indexed by dividing by tibia length (TL), and LV CO was indexed by dividing by tibia length to the power of three (TLeviously .max) and pressure decrease (dP/dtmin) was calculated and divided by maximal pressure (Pmax). End-diastolic pressure (EDP) and arterial elastance (Ea) were obtained from single-beats in steady state. After gradually decreasing preload by slow constriction of the inferior caval vein, end-systolic and end-diastolic elastance  were calculated by measuring the slope of the end-systolic and end-diastolic points of selected heartbeats.Invasive RV pressure-volume analysis was performed while intubated and ventilated with 2–3% isoflurane in oxygen as described previously . First, All animals were euthanized by exsanguination and extraction of the heart under inhalation of 2–3% isoflurane. The presence of pleural effusion, ascites, or visible liver edema/cirrhosis was registered. Cardiac weights  and TL were measured. Cardiac weights were indexed as described previously . The heaCardiomyocyte cross-sectional area (CCSA) was measured on wheat germ agglutinin (WGA) stained paraffin sections. Capillary/myocyte ratio was measured by dividing the counted amount of capillaries on five views of 100 × 100 μm by the expected amount of cardiomyocytes . For assessment of the amount of fibrosis, Masson’s trichrome staining  and Sirius red staining  was performed on paraffin whole sections of the heart, and analyzed using Image Scope 11 . The amount of fibrosis was quantified, per ventricle, as the blue-stained (Masson’s trichrome) or red-stained (Sirius red) percentage of the total tissue area, excluding major vessels. Pulmonary vascular histology was qualitatively assessed on Verhoeff stained paraffin sections of the left lung, based on previous experience . Macroph–ΔΔct method.RNA was isolated from snap-frozen tissue using Trizol reagent (Invitrogen) according to the manufacturer’s instructions and as described previously . cDNA wan = 5 per time point) and controls (n = 3 per time point) and normalized for protein concentration in each sample.The amount of cardiac ATP was assessed using ATP Assay Kit  following manufacturer’s instructions. Using colorimetric quantification, levels of ATP were determined in both ACS (Whole-tissue lysates were prepared with NP-40 lysis buffer containing phosphatase and protease inhibitors (Sigma-Aldrich), and western blotting was performed as described previously , 2019. Epost hoc correction. Linear regression was used to assess the correlation between gene expression of transforming growth factor beta (TGFβ) 1 and bone morphogenetic protein receptor 2 (BMPR2). A P value below 0.05 was considered as statistically significant.Statistical analyses were performed using GraphPad Prism 7.02. Since groups are too small to test whether the distribution of variables is normal, data are displayed as median ± interquartile range. Most variables are expressed as relative to control. In these cases, fold-change compared to the time point-matched control group was assessed, where after the control groups were pooled. In variables where using a relative unit was not preferable, control groups were compared. If no significant differences in time were observed, control groups were pooled. Comparisons between ACS and control, and between time points for ACS were performed using Kruskal–Wallis test. False discovery rate was controlled for by means of the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli as Although initially well tolerated at 1 and 3 m after surgery without clinical symptoms, 6 out of 8 rats demonstrated signs of severe clinical heart failure 6 months after ACS , RV end-diastolic pressure (EDP), and RV end-diastolic elastance (Eed) were not altered at any of the time points. Finally, RV Ees/arterial elastance (Ea) was significantly decreased after 6 months ACS. Heart rate was similar in ACS groups, compared to control.Results of invasive hemodynamics are displayed in ACS rats demonstrated progressive hypertrophy of both ventricles  and atri2+ ATPase 2a (SERCA2a), a regulator of intracellular Ca2+ that modulates excitation–contraction coupling  increased in both ventricles at all time points . Howevercoupling , remainecoupling . Phosphocoupling , remainecoupling . Levels coupling . Gene excoupling . Titin’scoupling . The N2BThe expression of TGFβ 1, a potent inducer of fibrosis, remained unaltered in the RV, but increased in the LV at 1 month and 6 months ACS . InteresThe present study demonstrates that the ACS rat model of long-term volume load leads to end-stage RV failure after 6 months. At this point, clinical signs of end-stage RV failure had developed , along with cardiac hypertrophy and severely impaired RV contractility. Furthermore, gradual decreases of both RV relaxation and LV contractility had occurred, which were relatively mild in comparison to the decrease in RV contractility. Myocardial fibrosis was, however, not observed, nor was activation of pro-fibrotic pathways. Our data add to the growing evidence that, different from LV failure, fibrosis is not a hallmark of RV failure associated with chronic volume overload.min), implicates RV failure due to decreased contractility. This is in contrast with the pressure-loaded RV, in which clinical symptoms of RV failure have been associated with diastolic, more than systolic dysfunction (The steep decrease of RV contractility (Ees) at 6 months, in contrast with the more gradual and less severe decrease of LV function, indicates that the symptomatic heart failure in the current model is predominantly driven by RV failure. Also, the significant decrease of RV contractility at 6 months, in contrast with the more gradual impairment of RV relaxation . Subsequently, this resulted in barely altered collagen gene expression and unaltered levels of phosphorylated SMAD2/3. This all is in accordance with the absence of increased protein levels of collagen, or fibrosis by histological assessment. Also, in both ventricles, TGFβ1 and BMPR2 expression were balanced, illustrated by their linear correlation. This balance and the unaltered levels of phosphorylated SMAD2/3 are also in line with the absence of myocardial fibrosis, as BMPR2 is an antagonist in the TGFβ fibrotic pathway, preventing fibrosis . At 6 moThese findings challenge the dogma that myocardial fibrosis, either as cause or consequence, is associated with volume load-induced end-stage RV failure. As discussed earlier, previous studies in models of RV pressure load have demonstrated that targeting RV fibrosis does not improve ventricular function  and thatThe absence of myocardial fibrosis in the present animal model of isolated volume load-induced RV failure, and the consequential lack of a relation with ventricular function, may have relevant consequences for the interpretation of imaging-based studies, reported earlier. These studies demonstrate indirect markers of increased fibrosis in the RV of human subjects with rTOF, who are often subjected to chronic RV volume load due to pulmonary valve incompetence . Now expmin, that apparently has not been caused by increased deposition of collagens. Previous reports on volume-loaded LV remodeling showed that not interstitial stiffness, but sarcomeric stiffness may be responsible impaired LV relaxation  has received fees for consultancy activities of RMB for Actelion and Lilly outside the content of this manuscript. The UMCG has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, Roche, Trevena, and ThermoFisher GmbH for projects of RAB, outside the content of this manuscript. RAB is a minority shareholder of scPharmaceuticals, Inc. and received personal fees from MandalMed Inc., AstraZeneca, Novartis, Servier, and Vifor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.