Ex vivo biaxial tests were performed in fresh sheep hearts. Histology and immunohistochemistry were performed to measure tissue collagen. The experimental data were then fitted to a Fung type model and a structurally informed model, separately. We found that the LV was stiffer in the longitudinal (outflow tract) than circumferential direction, whereas the RV showed the opposite anisotropic behavior. The anisotropic parameter K from the Fung type model accurately captured contrasting anisotropic behaviors in the LV and RV. When comparing the elasticity in the same direction, the LV was stiffer than the RV longitudinally and the RV was stiffer than the LV circumferentially, suggesting different filling patterns of these ventricles during diastole. Results from the structurally informed model suggest potentially stiffer collagen fibers in the LV than RV, demanding further investigation. Finally, type III collagen content was correlated with the low-strain elastic moduli in both ventricles. In summary, our findings provide fundamental biomechanical differences between the chambers. These results provide valuable insights for guiding cardiac tissue engineering and regenerative studies to implement chamber-specific matrix mechanics, which is particularly critical for identifying biomechanical mechanisms of diseases or mechanical regulation of therapeutic responses. In addition, our results serve as a benchmark for image-based inverse modeling technologies to non-invasively estimate myocardial properties in the RV and LV.Cardiac biomechanics play a significant role in the progression of structural heart diseases (SHDs). SHDs alter baseline myocardial biomechanics leading to single or bi-ventricular dysfunction. But therapies for left ventricle (LV) failure patients do not always work well for right ventricle (RV) failure patients. This is partly because the basic knowledge of baseline contrasts between the RV and LV biomechanics remains elusive with limited discrepant findings. The aim of the study was to investigate the multiscale contrasts between LV and RV biomechanics in large animal species. We hypothesize that the adult healthy LV and RV have distinct passive anisotropic biomechanical properties.  In both the U.S. and worldwide, structural heart diseases (SHDs) are the leading cause of death. The progression of SHDs is associated with unique ventricular biomechanical alterations that affect either single or double sides of the ventricles. Diastolic dysfunction is common in many SHDs and confers poor outcome in both the left and right ventricular diseases including heart failure with preserved ejection fraction and pulmonary hypertension. Despite the development of modern therapies, effective treatments for diastolic dysfunction in heart failure patients remain limited. As diastolic dysfunction is directly influenced by the passive biomechanical behavior of the myocardium, a detailed knowledge of this behavior could facilitate developing new therapeutic targets and personalized treatment approaches for diastolic dysfunction. Although several studies have characterized the passive biomechanics of the myocardium , these sUnder physiological conditions, the LV and RV experience dramatically different hemodynamic environments: while the LV experiences a high pressure, high resistance and low compliance circulatory system, the RV experiences a low pressure, low resistance and high compliance circulatory system. The RV has been long considered as a “compliant” chamber compared to the LV because of its larger chamber compliance, an extrinsic mechanical property calculated by ΔV/ΔP over a cardiac cycle . However, whether their intrinsic mechanical properties such as elastic modulus differ from each other remains a knowledge gap . Moreoven = 3 for RV). Since both human studies included samples from patients with and without cardiovascular diseases, the baseline information of healthy ventricles still remains unclear. Finally, healthy neonatal porcine hearts were examined by To date, there are only a few studies directly comparing the mechanical properties of the LV and RV. Among earlier studies, Humphrey et al. reported the equibiaxial mechanical behavior of the canine epicardium tissues . The strThe lack of baseline biomechanics data for LV and RV and particularly in large animal species has limited the expenditure of cardiac research in two main fields. Firstly, ventricular passive biomechanical properties can serve as a benchmark for image-based inverse modeling technologies to non-invasively estimate myocardial properties in the RV and LV . The imaK derived from the Fung type model. The structurally informed model indicated stiffer collagen fibers in the LV than the RV, which awaits further investigation. Furthermore, the elasticity at low strains was correlated with type III collagen content in both ventricles. These findings advance the fundamental understanding of the differences between LV and RV biomechanics, which can be used to guide cardiac tissue engineering and regenerative studies with chamber-specific mechanical environments and to develop the image-based inverse modeling technologies to non-invasively estimate myocardial properties in the ventricles.With the persistent need to establish computational tools for the estimation of large animal (including human) cardiac biomechanics and to guide cellular and tissue bioengineering research, the goal of this study is to compare the biomechanical properties of the LV and RV in healthy adults. We hypothesize that the adult healthy LV and RV have distinct passive anisotropic biomechanical properties. Sheep were chosen for their closer similarities to adult human anatomy, function, and physiology  than sman = 11) were obtained from 4+ year-old female sheep with no known cardiovascular disease or defects after the animals were euthanized for unrelated studies. Within 4 h of sacrifice, the tissues were immersed in physiological saline solution (PBS) at room temperature until mechanical testing  was dusted onto the sample for strain characterization. Before testing, approximately 0.1 N of force was applied to pre-load the tissue in both directions. Next, biaxial testing was performed at two different displacement ratios  in random order (2:1 and 1:2) and then at an equibiaxial test (2:2). The first ratio test was completed with 15 cycles including preconditioning cycles. The following ratios’ tests were completed with eight cycles per ratio. Finally, the first ratio test was repeated to confirm that no tissue damage occurred. Data acquisition was performed with an in-house LabVIEW program  at one fps and tissue deformations were obtained by digital image correlation (S) stresses, and Green strain (E) were calculated for each direction  were derived as the slopes of the stress-strain curves at the low and high strain ranges  (M/ε in the low or high strain range was used to assess the modulus (M) normalized by the maximal Green strain (ε) in the corresponding strain range and the respective direction  . Then, tirection .tissue-level stiffness and anisotropic behavior in the LV and RV in a comparative manner; and the structurally informed model was used to provide insights into the differences between fiber-level mechanical and architectural properties of the LV and RV myocardium. An affine deformation was assumed within the samples under equibiaxial loading as commonly adopted in biaxial soft tissue testing.Next, we fitted our equibiaxial experimental data to a phenomenological constitutive model (Fung type model) and a structurally informed model. We used the phenomenological Fung type model to assess the overall kLC and kCL from our experimental data. . The shear deformation was minimal compared to the in-plane stretches along longitudinal (OT) and circumferential (cross-OT) directions. Accordingly, shear stresses were assumed to be negligible in our modeling work.We calculated the shear deformations al data. . The shE) components were calculated as:Furthermore, the relevant Green strain tensor  = 1, and B are the material constants. The stress-strain relationships in the L and C directions were derived as:The second P-K and Cauchy stresses for an incompressible tissue were calculated as:K and elasticity at zero load in two directions  was calculated to assess the fitting results. Finally, the anisotropic parameter  studies .ground matrix , myo- and collagen fibers, respectively, and Next, we used a structurally informed model that incorporates the transmural changes of myo-/collagen fibers to reveal the contributions of each fiber type to the tissue-level myocardial biomechanical behavior . BrieflyS) was described in terms of the energy function At the tissue level, the 2nd P-K stress tensor , the tissue blocks were further sectioned into 4–8 serial sections (∼125 µM apart) from the epicardial to endocardial side and stained for fiber orientation measurement.After biaxial testing, the samples were fixed in 10% buffered formalin and embedded in paraffin for collagen content measurement. In some samples (via a transmission microscope (Nikon Eclipse E800) and Image Pro Premier software  for collagen content quantification. For each sample, three regions were randomly selected under polarized light microscopy. An image thresholding method in which yellow, green, brown and dark blue colors were chosen to represent type I collagen, type III collagen, ground matrix and muscle, respectively. The amounts of type I and III collagen were quantified as the area percentage to total tissue area, and the amount of collagen content was quantified as the total area percentage of type I and III collagen (The tissue slices were stained with Picrosirius Red (PSR) and imaged and analyzed collagen .n = 4) and RV (n = 4) samples to confirm the area fraction measurement of type III collagen in PSR staining slides. Tissue samples were stained with rabbit polyclonal anti-human collagen III antibody . Image thresholding via ImageJ  was used to determine the area fraction of collagen III.We further performed immunohistochemistry (IHC) to LV  were performed with the Wilcoxon signed-rank test for the paired equibiaxial data. For all other statistical comparisons, the Mann-Whitney U test was used for the unpaired data. Pearson correlation analysis was performed to investigate the correlations between the modeling parameters or collagen content and mechanical properties. All analyses were performed in GraphPad Prism (v8.0.2). Data are presented as mean ± SEM and The average stress-strain curves from equibiaxial tests are shown in M than the RV for the non-equibiaxial tests (p = 0.052). At the high strains, the LV had a higher M or M/ε than the RV in the longitudinal direction, whereas the RV had a higher M or M/ε than the LV in the circumferential direction , and the fitting results are summarized in ). Expectedly, the anisotropic parameter K was significantly different between the LV and RV (p < 0.01). Finally, we performed correlation analyses and found that K was significantly correlated with the ratios of longitudinal to circumferential elastic moduli (M and M/ε) in both strain ranges .We further compared the zero-load modulus ntricles . ExpectEub) than that of the RV.We fit the equibiaxial stress-strain curves with the structurally informed model to investigate the different contributions of myocardial components (myo- and collagen fibers) to tissue mechanics in these chambers. The fitting results are summarized in p < 0.1). Our immunohistochemistry measurement of collagen III isoform agreed with the polarized light PSR measurement in collagen III. Furthermore, we observed a significant correlation between type III collagen percentage and the longitudinal M (ML) at the low-strain range in all samples (p < 0.05). In addition, we observed a significant correlation between the total collagen and circumferential M/ε at the high-strain range (p < 0.05). The complete results of all correlations between the collagen content and mechanical properties of the LV and RV are summarized in Next, we examined the difference in collagen content between the LV and RV. There were trends of higher total collagen and type I collagen contents in the RV compared to the LV , p < 0.1K derived from the Fung type model provided consistent finding in the opposite anisotropy of LV and RV as observed experimentally; ; in contrast, the RV is crescent shaped and is comprised of wrap-around transverse fibers that deforms more longitudinally   . Thus, oTo date, discrepant findings are reported on the comparison of elasticity of the LV and RV. Please note that the intrinsic mechanical property measurements should be distinguished from the general “consensus” that the RV is a more compliant chamber . In human myocardium, the RV tissue tended to achieve higher wall stresses in both biaxial axes compared to the LV tissue, but whether the difference reached statistical significance is unknown . In cont). Because of the different trends of comparison at different directions, it is not appropriate to simply conclude that the “LV is stiffer than the RV” or vice versa at the tissue level. Moreover, the heterogenous organization of myofiber layers and the nonlinear, anisotropic nature determine that one cannot refer to a single value of mechanical parameter  to describe the myocardium. Unfortunately, such knowledge has not been well recognized by emerging fields like cell and tissue engineering for cardiac research. There are also mixed citations of “tensile” and “compressive” elastic modulus to represent the stiffness of myocardium. As a result, a variety of elastic moduli (from ones of kPa to tens of MPa) has been adopted for the matrix or bioscaffold to simulate ventricles in the tissue engineering or mechanobiology studies . Our results showed that the RV was stiffer than the LV in the circumferential direction, and the opposite trend of difference  was shown in the longitudinal direction , 3. Bec studies . Lastly,The phenomenological computational models typically provide good capture of the macroscopic mechanical behavior; however, they lack detailed information on the structural and material properties of the myocardium constituents . InsteadML in all ventricles and at low strains (p < 0.05). This indicates that the longitudinal elasticity partly stemmed from type III collagen recruitment. It is known that type III collagen is mesh-like in structure and more compliant than fibrillar type I collagen (M/ε in both ventricles and at high strains (p < 0.05). The strong influence of collagen fibers in high-strain elasticity is likely the outcome of more fully recruited collagen at larger deformation.In this study, we also found novel correlations between collagen and ventricular biomechanics. Firstly, we observed a trend of higher collagen content including type I collagen in the RV compared to the LV. This is consistent with the prior report of collagen content in human LV and RV determined from hydroxyproline assays . Second,collagen , but howcollagen . It is aex vivo mechanical measurement of myocardium from large animals or human patients due to a large tissue size. Prior studies typically sectioned the LV into two or three layers  direction and the RV being stiffer in the circumferential (cross-OT) direction. Interventricular comparison showed that the RV was more compliant than the LV in the longitudinal direction and was stiffer than the LV in the circumferential direction, which suggests different impacts of passive mechanics of these ventricles on the blood filling during diastole. These anisotropic properties were captured by the zero-load elastic moduli as well as the anisotropic parameter


Anabolic steroid (AS) use is common in young males, with several reports of various adverse cardiovascular events in the users of AS. We present a unique case of a young male with no other risk factors who developed dilated cardiomyopathy secondary to abuse of AS. The exact mechanism by which AS leads to cardiomyopathy is not very well understood. No specific guidelines have been developed yet with regard to the management of AS-induced cardiomyopathy currently. Adverse events from AS must be promoted to increase awareness in the general and medical population. Anabolic steroid (AS) abuse is a common problem encountered in body builders. These agents may lead to structural changes in cardiac muscle through their action on androgen receptors present on cardiac myocytes. These may cause myocardial toxicity by inducing tissue fibrosis and apoptosis ,2.AS-induced cardiomyopathy is not very commonly encountered in the routine practice, and the mechanism behind it is not well understood currently. More research is needed to understand the long-term implications of AS on the cardiovascular system -3.A 29-year-old male with a history of AS use disorder presented with progressive shortness of breath with moderate exertion. He reported ongoing dyspnea with moderate intensity exertion for the preceding several weeks, limiting his vigorous routine exercise regimen with fatigue. He denied any orthopnea, paroxysmal nocturnal dyspnea, recent weight gain or weight loss, chest pain, dizziness, presyncope, syncope, or diaphoresis. He denied any dyspnea at rest or with mild or minimal exertion. He reported his continued ability to perform his routine exercise, which included weight-lifting, although it was getting more difficult for him to continue exercising at the same intensity due to fatigue and dyspnea more than his usual state of health with moderate-intensity physical exertion.He was diagnosed to have dilated cardiomyopathy based on a transthoracic echocardiogram showing severely dilated left ventricle, severely decreased left ventricular ejection fraction of 21.7% with global hypokinesis along with grade 3 diastolic dysfunction, and normal right ventricular structure and function. His right ventricular ejection fraction was normal. There was no left ventricular hypertrophy and no evidence of valvular dysfunction on echocardiogram. He reported injecting ASs at a dose of at least 1 mg in each extremity every day for the preceding eight months. His serial cardiac biomarkers were negative. His chemistry panel and brain natriuretic peptide level were within normal limits. His complete blood cell count showed polycythemia but a normal white cell count and a lipid profile showed borderline dyslipidemia (Table His electrocardiogram (ECG) showed sinus rhythm, left anterior fascicular block, T wave inversions in inferior leads, V5, and V6, and borderline ST segment elevation in V1-V3 with reciprocal mild ST segment depression in the inferior leads from early repolarization pattern (Figure There was no family history of cardiomyopathy. There were no clinical signs of a viral illness. No history of a recent viral illness was reported. Cardiac catheterization was not pursued despite newly diagnosed severely reduced left ventricular systolic function based on patient preference. Given the history of significant AS use and the patient being agreeable to completely remain abstinent from any further AS use, he elected an approach to reassess his left ventricular function after remaining completely abstinent to AS use.He was started on guideline-directed medical management for his dilated cardiomyopathy with reduced systolic function with an angiotensin-converting enzyme inhibitor and a cardioselective beta-blocker. He was counseled on strict abstinence from alcohol, illicit substances, and AS abuse. He will be followed as an outpatient.Various studies have noted an association between AS abuse and development of hypertension, left ventricular hypertrophy with fibrosis, sudden cardiac death, atrial and ventricular arrhythmias, myocardial infarction, stroke, accelerated atherosclerotic cardiovascular disease, and induction of a hypercoagulable state. Longstanding use of AS has been linked to both systolic and diastolic myocardial dysfunction in young individuals with otherwise low risk for cardiovascular disease. AS-induced systolic dysfunction may be reversible after complete cessation of AS use; however, diastolic dysfunction may not be fully reversible -7.Anabolic steroidal agents are known to alter lipid metabolism, increase low-density lipoprotein, lower high-density lipoprotein concentration, and may lead to polycythemia by stimulating erythropoiesis, all of which were noted in our case ,4.There are no specific guidelines currently regarding the approach for the management of AS-induced cardiomyopathy. Definitive management for AS-induced cardiomyopathy involves complete cessation of the offending AS agents and initiation of conventional heart failure therapy. Use of beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers are the first-line agents for cardiomyopathy with systolic dysfunction in general as these agents reverse left ventricular dilation ,5,7,8.Left ventricular dysfunction due to AS use may continue to progress and eventually become irreversible after longstanding abuse of these agents. Close clinical investigation is needed to understand the possible underlying etiology of mechanism behind cardiotoxic effects of these agents leading to potentially irreversible cardiac damage ,7,9,10.The abuse of AS needs to be strictly prohibited given the possibility of significant and potentially irreversible cardiovascular damage in young individuals with otherwise low risk factors for cardiovascular disease. Our case might provide an evidence of an association between AS abuse and development of heart failure given the fact that he did not have any historically known risk factors for the development of dilated cardiomyopathy.


ROC analysis demonstrated RACI to be the best overall predictor of a high-risk Importance Factor Score . Older age at the time of repair and a diagnosis of pulmonary atresia were associated with a larger RACI. Automated atrial CMR measurements are easily obtained from standard CMRs and have the potential to serve as noninvasive predictors of adverse outcomes in rTOF. Atrial size and function have been recognized as markers of diastolic function, and diastolic dysfunction has been identified as a predictor of adverse outcomes in repaired tetralogy of Fallot (rTOF). This was a retrospective single-center study with the objective of investigating the use of atrial measurements obtained via CMR for predicting outcomes in rTOF patients. Automated contours of the left and right atria (LA and RA) were performed. A novel parameter, termed the Right Atrioventricular Coupling Index (RACI), was defined as the ratio of RA end-diastolic volume to right ventricle (RV) end-diastolic volume. Patients were risk-stratified using a previously validated Importance Factor Score for the prediction of life-threatening arrhythmias in rTOF. Patients with a high-risk Importance Factor Score (>2) had a significantly larger minimum RA volume ( Over the past several decades, there has been significant improvement in surgical techniques and post-operative care for patients with tetralogy of Fallot (TOF). This has led to a growing population of patients living with repaired TOF (rTOF). Despite improvements in early mortality, there is still a relatively high incidence of morbidity and mortality late after repair, beginning primarily in the third decade of life ,2. Late RV size and systolic function have therefore been the primary areas of focus when assessing the timing of pulmonary valve replacement (PVR) and long-term outcomes . HoweverDiastolic dysfunction has emerged as an important predictor of adverse outcomes in multiple forms of congenital heart disease . In rTOFAnother recently devised CMR prognostic tool, the left atrioventricular coupling index (LACI), has been evaluated as part of the Multi-Ethnic Study of Atherosclerosis (MESA) . LACI isThere has been limited investigation intof the use of atrial measurements obtained via CMR for predicting outcomes in rTOF patients. Thus, we examined the relationship between left and right atrial volumes and function and ventricular parameters from CMR. We also determined the association of atrial measurements and atrioventricular coupling with the risk of adverse long-term outcomes using an established risk score. Additionally, we assessed the association of atrial CMR parameters with pulmonary valve replacement.A database search identified all rTOF individuals older than 10 years of age who had a CMR study at the Children’s Hospital of Pittsburgh or the UPMC Presbyterian Hospital between 2011 and 2020. A total of 63 patients were included in the study. This study was approved by the University of Pittsburgh Institutional Review Board and was conducted in compliance with the Health Insurance Portability and Accountability Act. The requirement for informed consent was waived due to the retrospective nature of the study.Demographic and clinical data were obtained from electronic medical records. These included patients’ surgical and procedural histories as well as long-term outcomes, such as death, hospital admissions, and the need for implantable cardioverter defibrillator (ICD) placement.CMR studies were performed using GE HDxT 1.5 Tesla scanners  or Siemens Sola 1.5 Tesla scanners . Briefly, ventricular assessment was performed using electrocardiographically gated, balanced steady-state free precession (bSSFP) cine CMR in vertical and horizontal ventricular long-axis planes. Standard 2- and 4-chamber cine images were imported into post-processing software . Ventricular volumes and function were measured by tracing the endocardial and epicardial borders on each short-axis bSSFP cine slice at end-diastole  and end-systole . The pulmonary regurgitation fraction was computed based on standard 2-dimensional phase-contrast imaging positioned in the main pulmonary artery. Automated biplane atrial function evaluation was performed to measure left atrial (LA) volumes; contours were adjusted manually as needed. The right atrial (RA) volumes were measured from monoplane 4-chamber views . LA and 2. The TOF repair was considered complex if it required an RV-to-pulmonary-artery (PA) conduit rather than a transannular patch. This score was modified slightly based on the available data. We did not include the presence of moderate-to-severe RV pressure load, as these data were not available; this parameter was worth a maximum of 1 point and minimally contributed to the total score. An Importance Factor Score >2 was considered high risk. A previously established Importance Factor Score was calculated for each patient. This score includes the following variables: the presence of symptoms, LV dysfunction, RV dysfunction, RV pressure load, age at repair, history of shunt pre-repair, complexity of repair, QRS duration ≥180 ms, and evidence of ventricular tachycardia. Left ventricular dysfunction (moderate to severe) was considered as an LVEF less than 45%, as previously defined. Right ventricular dysfunction (moderate to severe) was defined as an RVEF less than 40%. Moderate-to-severe RV volume load was defined as an RVEDVi greater than 130 mL/mA new risk score was also calculated for each patient and was termed the “RV-Independent Score”. This score was similar to the Importance Factor Score described above, with 2 exceptions. First, right ventricular end-diastolic volume was not included in the formula in order to investigate whether RA volume correlated with the risk score independently of RV volume. Second, a QRS duration of ≥120 ms was used as a cutoff point instead of 180 ms because our population was relatively young and none of our patients had a QRS duration >180 ms. The cutoff point of 120 ms was chosen given that this is the QRS duration for diagnosis of a right bundle branch block. Additionally, approximately one-third of our population had a QRS duration below 120 ms. An RV-Independent Score >2 was considered high risk.Based on prior studies demonstrating the prognostic value of LACI ,13,14, wU tests were used for comparison of non-normally distributed independent categorical variables and dependent continuous variables. The t-test was used for normally distributed variables. Univariable associations between continuous variables were determined using the Spearman correlation. Receiver-operating characteristic (ROC) curves were generated to evaluate the ability of CMR parameters to predict a high-risk Importance Factor Score. Statistical analyses were performed using commercially available software  and SPSS v27.0 ). Two-tailed p < 0.05 was considered statistically significant.Continuous data were summarized as medians , and categorical data were summarized as N (%). The Kruskal–Wallis and Mann–Whitney 2 and a median pulmonary regurgitation fraction of 39  percent. The median RACI was 15.0 (IQR 10.5–22.1) percent : 0.4, 1.0) years, and the median age at the time of CMR was 16.4  years. CMR data were notable for a median indexed right ventricle end-diastolic volume (RVEDVi) of 119.1  mL/m percent .p = 0.04) and RACI (p = 0.03) . The remainder of the atrial CMR measurements did not significantly differ between these diagnoses. There were no significant differences in atrial CMR measurements between patients with and without a history of a BTT shunt (Older age at the time of TOF repair was associated with a larger maximum RA volume ( = 0.03) . PatientTT shunt .p = 0.03), and LA ejection fraction was positively associated with both a higher LVEF (p = 0.02) and RVEF (p = 0.02) (p = 0.0007) and a reduced pulmonary regurgitation fraction (p = 0.0002)  . A large 0.0002) .2, p = 0.04 and 18.6  vs. 13.5  percent, p = 0.03, respectively) (p = 0.03), superior to RVEF and RVEDVi  had a significantly larger minimal RA volume and RACI compared to patients with an importance factor ≤2  vs. 16.6  mL/mctively) . ROC anad RVEDVi .2, p = 0.02 and 19.5  vs. 13.1  percent, p = 0.02, respectively)  had a significantly larger minimal RA volume and RACI compared to patients with a score ≤2  vs. 15.4  mL/mctively) .With regards to long-term outcomes, patients had a median follow-up time of 5.8 years from the time of CMR. There were no deaths in this cohort. Only one patient required ICD placement and hospitalization for arrhythmias; this patient had a maximum LA and RA volume greater than the 70th percentile and an RACI greater than the 98th percentile. One patient required hospitalization for management of congestive heart failure symptoms; this patient had a minimum and maximum RA volume greater than the 90th percentile, with an RA EF less than the 5th percentile and an RACI greater than the 85th percentile.2, p = 0.03). When comparing the 25 patients who underwent PVR after the CMR with those who did not, those who underwent PVR had a significantly lower LA ejection fraction  vs. 60.4  percent, p = 0.03). None of the other parameters were different between the groups.Thirty-one patients (49%) underwent PVR (6 patients before CMR and 25 patients after CMR). For the six patients who underwent CMR following PVR, the average length of time from PVR to CMR was 6.6 years. When comparing the six patients who had undergone PVR prior to the CMR with the rest of the cohort, the maximum RA volumes were larger in the patients with PVR  vs. 27.6  mL/mOur study evaluated the association of automated atrial CMR measurements with patient characteristics, ventricular CMR parameters, and timing of PVR. We also sought to determine the relationship between these atrial parameters and adverse outcomes via an Importance Factor Score surrogate. We found that patients with a high-risk Importance Factor Score (>2) and a high-risk RV-Independent Score (>2) had a larger minimum RA volume and RACI compared to those with scores ≤2. RACI had the highest area under the curve for prediction of a high-risk Importance Factor Score. Older age at the time of TOF repair and a diagnosis of pulmonary atresia were associated with a larger RA volume and a larger RACI. Larger LA and RA volumes were associated with a larger LVEDVi and LVESVi. Finally, patients post-PVR had a larger maximum RA volume compared to those without PVR at the time of CMR. Patients who underwent PVR after CMR had significantly lower LAEF according to CMR compared to subjects who did not ultimately undergo PVR.Similar to our study, Ait Ali et al. showed that RA dilation was associated with all-cause mortality, aborted sudden cardiac death, and sustained VT in a cohort of 165 patients with rTOF . HoweverIn this study, we used a previously validated Importance Factor Score as a surrogate for long-term adverse outcomes. We also developed a new risk score modeled on this established score called the RV-Independent Score. This score excluded RVEDVi in order to investigate whether atrial parameters remained significant independently of RV volume. In addition, we adjusted the QRS duration cut off from ≥180 ms to ≥120 ms, which is the QRS duration for a diagnosis of a right bundle branch block. Multiple previous studies, including our recent meta-analysis, have demonstrated that a QRS duration >180 ms and increased RV end-diastolic volume are not associated with mortality or sudden cardiac death in the current era. However, QRS duration as a continuous variable was associated with mortality in rTOF . PreviouWe also evaluated the concept of atrioventricular coupling in this study. Our results demonstrate that both RA and LA volumes correlate with LV volume, and RA and LA ejection fractions correlate with LV ejection fraction. Interestingly, we did not find a similar relationship between RA volume and ejection fraction with RV volume and ejection fraction. This is likely due to the presence of pulmonary regurgitation in many of our patients, which is known to affect RV volume and function in rTOF ,20.RACI was used as a new predictive tool in our study based on previous findings demonstrating the value of LACI for predicting cardiovascular outcomes in adult populations. RACI relates RA to RV volume, thereby providing a measurement that acknowledges the important interactions that exist between RA and RV performance . In thisRACI is also inversely related to RA ejection fraction and pulmonary regurgitation (PR) fraction. This latter finding is likely secondary to the known physiological changes associated with chronic PR, which leads to progressive RV enlargement and dysfunction . This inAlthough this study demonstrates important findings related to the use of CMR atrial parameters in the rTOF population, there are several inherent limitations. These limitations include its retrospective design and relatively small sample size derived from a single center. Larger, multi-center studies will be needed to validate our results. This would allow for a more direct assessment of the relationship between atrial CMR parameters and long-term outcomes rather than using a surrogate risk score. We used an established Importance Factor Score that has previously been found to be associated with malignant arrhythmias in rTOF patients in order to mitigate this limitation. An additional limitation is the understanding that CMR may not be an accessible test in some settings. It may be useful to evaluate atrial and RACI measurements obtained via echocardiography, particularly in the setting of increasing utilization of three-dimensional echocardiography. Finally, patients with epicardial leads were excluded from this study, as CMR is not deemed safe for this population.The results of this study demonstrate that automated atrial volumes and ejection fractions have the potential to serve as additional non-invasive predictors of adverse clinical outcomes in rTOF. This study also highlights the potential benefits of a novel RACI parameter for evaluating atrioventricular interactions and risk-stratifying patients. Patients with a high RACI are at higher risk and may require closer monitoring for the development of adverse outcomes.


Myocardial strain imaging has gained importance in cardiac magnetic resonance (CMR) imaging in recent years as an even more sensitive marker of early left ventricular dysfunction than left-ventricular ejection fraction (LVEF). fSENC (fast strain encoded imaging) and FT (feature tracking) both allow for reproducible assessment of myocardial strain. However, left-ventricular long axis strain (LVLAS) might enable an equally sensitive measurement of myocardial deformation as global longitudinal or circumferential strain in a more rapid and simple fashion.In this study we compared the diagnostic performance of fSENC, FT and LVLAS for identification of cardiac pathology  in patients presenting with chest pain . Patients were prospectively recruited from the chest pain unit in Heidelberg. The CMR scan was performed within 1 h after patient presentation. Analysis of LVLAS was compared to the GLS and GCS as measured by fSENC and FT.In total 40 patients were recruited . LVLAS was comparable to fSENC for differentiation between healthy myocardium and myocardial dysfunction , while FT-derived strain did not allow for differentiation between ACS and non-cardiac patients. There was significant variability between the three techniques. Intra- and inter-observer variability (OV) was excellent for fSENC and FT, while for LVLAS the agreement was lower and levels of variability higher .While reproducibility was excellent for both FT and fSENC, it was only fSENC and the LVLAS which allowed for significant identification of myocardial dysfunction, even before LVEF, and therefore might be used as rapid supporting parameters for assessment of left-ventricular function. Strain imaging has gained importance in cardiac magnetic resonance (CMR) imaging in recent years. It allows for very sensitive assessment of myocardial deformation and has been shown to detect subclinical changes in patients with a variety of underlying cardiac conditions such as hypertrophic cardiomyopathy, cardiotoxic cancer therapy patients, ischemic heart disease, heart failure, atrial fibrillation, hypertension, or valvular heart disease . FurtherSeveral methods exist for strain measurement: recent more rapid techniques include fast-strain encoded imaging (fSENC), feature tracking (FT) and left-ventricular long axis strain (LVLAS).fSENC uses tag lines that are oriented parallel to the imaging plane from which color-coded images can be generated .A disadvantage of fSENC imaging is the non-measurable radial strain and the need for a separate image acquisition sequence and assessment software. However, it has been proven to be highly reproducible  and alloFT enables the measurement of strain by tracing anatomic elements along the cavity-myocardial interface in cine images. Therefore, no additional images need to be acquired and retrospective analyses of pre-existing datasets can be performed. A disadvantage, however, is its susceptibility to through-plane motion artefacts and partial volume effects . HoweverA recently emerging parameter for LV functional assessment is the LVLAS. It has been shown that the major portion of stroke volume is generated by the longitudinal atrioventricular plane movement . As suggAll these different strain imaging techniques have their individual advantages and pitfalls, yet no direct comparison of LVLAS to FT/fSENC has been performed so far.The purpose of this study was to assess and directly compare both GLS  and GCS  using fSENC and FT as well as LVLAS within a study population of patients presenting with chest pain. We aimed to explore the diagnostic performance of the different strain techniques for identification of myocardial dysfunction (acute coronary syndrome (ACS) or underlying cardiac pathologies) as well as evaluate correlation of GLS and GCS between the three strain imaging tools.Furthermore, we hypothesized that LVLAS is comparable to fSENC or FT for LV-function assessment and offers a rapid analysis of myocardial deformation in a simpler and clinically applicable fashion.Patients were prospectively recruited from the chest pain unit of the University Hospital in Heidelberg using a randomized double-blinded single-center study design (consecutive sampling). The inclusion and exclusion criteria for patient enrolment is provided in Table The CMR scan was performed within a one-hour timeframe before the 2nd hscTnT measurement . PatientCMR scans were all performed in a 1.5 Tesla whole-body CMR scanner . A vector ECG was applied for R-wave triggering.Standard SSFP cine function images: long axis (LAX)  and short axis (SAX) 2, TE 1.38 ms, TR 2.77 ms, flip angle 60°, pixel size 0.88 × 0.88 mm2, 35 acquired phases, slice thickness 8 mm) and SAX 2, TE 0.71 ms, TR 12.16 ms, flip angle 30°, pixel size 1 × 1 mm2, slice thickness 10 mm) was applied. Using the “Tissue Tracking” module, GCS and GLS were semi-automatically calculated by averaging peak strain values of individual segments based on the 16-segment model. We also performed a sub-analysis based on artificial intelligence (AI) automated contouring  by the software Myostrain® . GCS and GLS were reported and represented in color-coded bull’s-eye plots according to the American Heart Association 16-segment model. Longitudinal strain was derived from the SAX images, whereas circumferential strain was gained from the LAX images  and end diastole (ED) using the following formula Fig. c:\docume20 scans for FT and 15 scans for fSENC as well as LVLAS measurement were randomly selected and separately analyzed a second time by the lead study investigator after a period of more than 6 months  as well as another unbiased investigator. All observers are certified experienced readers and were blinded to patients’ final clinical diagnoses.The reference standard was based on the patient’s final clinical diagnosis as determined by staff cardiologists blinded to our results. Final diagnosis was derived from serial hscTnT testing  and, ifThe primary endpoint of this study was to assess the diagnostic performance of LVLAS in comparison to the more established parameter GLS.0: LVLAS is less accurate at identifying cardiac dysfunction in patients with chest pain than GLS by fSENC and FT.Therefore, the null hypothesis was formulated as HFor all statistical analyses the software programs Excel , SPSS  and MedCalc  were used.Quantitative data is represented with mean values and standard deviation (SD). Receiver Operating Characteristic (ROC) curves were calculated and the area under the curve (AUC) was determined. ROC curves were compared using the Hanley and McNeil test . The datIn total, we prospectively recruited 40 patients with chest pain. Of these 40 patients 6 were found to have ACS , another 6 had an underlying cardiac, non-ACS disease , while the remaining 28 were determined to have no cardiac cause of the chest pain. Patient characteristics are depicted in Table All CMR scans were performed with a mean study time of 19.5 ± 5.3 min, including patient preparation and scan time.ROC curves were drawn for differentiation between cardiac pathology (6 ACS patients and 6 patients with underlying cardiac disease) from non-cardiac chest pain (n = 28).p < 0.025; GCS-FT vs. GLS-fSENC p < 0.035), whereas for the other parameters the difference was not significant  closely followed by GLS-fSENC AUC: 0.882). Notably, LVLAS achieved good results with an AUC of 0.771, while FT strain values demonstrated the weakest performance . GCS-FT differed significantly from GCS- and GLS-fSENC curves  and the GLS and GCS  as well as LVLAS compared between the three patient groups. Results are depicted in Fig. p < 0.005; LVLAS: p < 0.02) differentiate between non-cardiac (0) and underlying cardiac disease patients (2).All strain parameters could significantly (fSENC/FT: p < 0.0025), GLS-fSENC (p < 0.025) and LVLAS (p < 0.05) all allowed for significant differentiation between non-cardiac (0) and ACS patients (1), further separation between ACS (group 1) and other cardiac diseases (group 2) was only possible with GLS-fSENC (p < 0.006). GCS- and GLS-FT while not allowing for distinction between non-cardiac (0) and ACS (1) patients, were significantly different between ACS (1) and cardiac, non-ACS (2) patients (p < 0.02).While GCS-fSENC (p < 0.05). Linear regression analyses are depicted graphically in scatter plots . The correlation was strongest, albeit weak, between GLS-fSENC and GLS-FT (R2 = 0.408).Correlation coefficients (Pearson and ICC) for the different myocardial deformation parameters are given in Tables ots Fig.  showing Bland–Altman plots revealed similar levels of variability for GLS  and LVLAS . Variability was lowest between GLS as derived by fSENC compared to FT (CoV 18.18%).p < 0.05). In a ROC curve analysis, the functional parameters showed a weak performance with the LVEDV demonstrating the highest AUC amongst them for identification of myocardial dysfunction . In a further analysis we correlated the different strain values to LVEF and LVESV/LVEDV. All strain parameters  correlated significantly (p < 0.05) to the LVEDV whereas for LVEF and LVESV it was only GLS-FT and GCS-FT which correlated significantly (p < 0.05).We performed a separate analysis regarding the diagnostic accuracy of LVEF, LVESV and LVEDV within our patient cohort. All three values did not allow for significant differentiation between the three patient groups (0: non-cardiac/1: ACS/2: cardiac-non-ACS). Only the LVEDV could significantly distinguish between group 0 and group 2 (p < 0.005). Correlation, limits of agreement (LoA), biases and coefficient of variation (CoV) are depicted in Figs. Intra- and inter-observer reliability was excellent for FT (Pearson and ICC > 0.85). Strain values derived by automated contours using AI tools were similarly reproducible (Pearson and ICC > 0.85). All data were statistically highly significant (p < 0.005). Correlation, limits of agreement (LoA), biases and coefficient of variation (CoV) are depicted in Fig. Intra- and inter-observer reliability for fSENC was excellent and comparable to that of FT (Pearson and ICC > 0.8). All data were statistically highly significant (p < 0.005). Correlation, limits of agreement (LoA), biases and coefficient of variation (CoV) are depicted in Fig. While intra-observer reliability was slightly higher  than inter-observer reliability , the LVLAS showed lower levels of correlation than FT or fSENC-derived strain values. The correlation data was highly significant  within a study population of patients with chest pain.LVLAS was comparable to fSENC-derived strain for differentiation between healthy myocardium (non-cardiac chest pain) and myocardial dysfunction (ACS and underlying cardiac pathology) while FT-derived strain showed the weakest performance.GLS-fSENC was the only parameter which allowed for significant patient triage according to final diagnosis .There was significant variability between the three techniques with moderate correlation of GCS and GLS (FT/fSENC) to LVLAS.Functional parameters  were less susceptible than strain for identification of cardiac pathologies.Intra- and inter-observer agreement and variability of global strain values were excellent for FT and fSENC.LVLAS showed lower levels of intra- and inter-observer agreement and higher variability than FT or fSENC.The main findings of our study are the following:LVLAS is a relatively new method for assessing global left ventricular function – allowing significant discrimination of patients with cardiomyopathies from healthy subjects . AlthougInterestingly, within our study population LVLAS allowed for similar differentiation between cardiac pathology and non-cardiac disease as fSENC-derived global strain values and demonstrated a better performance than FT. ROC curves did not differ significantly from each other due to the small sample size of patients deemed to be suffering from cardiac pathology and need to be evaluated in a bigger patient population. This data is promising and highlights the usefulness of LVLAS as a rapid alternative approach for the assessment of ventricular function.FT-derived regional strain has been shown to allow differentiation between areas of myocardial scar and healthy myocardium . We wereCorrelation between the three modalities was moderate with high variability. GLS-FT and GLS-fSENC showed the best correlation  with the least variation (CoV = 18.18%). This confirms previous data showing that differences in image acquisition and post-processing analysis may ultimately lead to substantial bias , 41. TheIn general, functional parameters such as LVEF, LVESV and LVEDV per se did not allow for significant identification of the underlying cardiac pathologies within our study cohort. This is in line with previous studies which have indicated that strain is a more sensitive marker of early left ventricular dysfunction than left-ventricular ejection fraction (LVEF) , 43. IntIntra- and inter-observer analysis was excellent for both FT and fSENC with low levels of variation. However, correlation was lower for LVLAS intra-/inter-observer reliability with higher variation. This stands in contrast to the previous data by Riffel et al. which showed low levels of variability  within a larger patient cohort consisting of 40 healthy volunteers and 125 cardiomyopathy patients . This diThe main limitation of our study is the relatively small sample size. Additionally, findings were not compared to standard CMR protocols or echocardiographic derived strain data. No extended follow-up was performed—prospective studies are required to evaluate LVLAS as a prognostic parameter.While reproducibility was excellent for both FT and fSENC. It was only fSENC and the LVLAS which allowed for significant identification of myocardial dysfunction, even with preserved LVEF, and therefore might be used as additional parameters for the assessment of left-ventricular function.


Developments in myocardial perfusion cardiovascular magnetic resonance (CMR) allow improvements in spatial resolution and/or myocardial coverage. Whole heart coverage may provide the most accurate assessment of myocardial ischaemic burden, while high spatial resolution is expected to improve detection of subendocardial ischaemia. The objective of this study was to compare myocardial ischaemic burden as depicted by 2D high resolution and 3D whole heart stress myocardial perfusion in patients with coronary artery disease.2) and 3D whole heart  stress CMR at 3-T in randomized order. Myocardial ischaemic burden (%) was visually quantified as perfusion defect at peak stress perfusion subtracted from subendocardial myocardial scar and expressed as a percentage of the myocardium. Median myocardial ischaemic burden was significantly higher with 2D high resolution compared with 3D whole heart . There was excellent agreement between myocardial ischaemic burden , with mean ratio difference between 2D high resolution vs. 3D whole heart 1.28 ± 0.67 (95% limits of agreement −0.03 to 2.59). When using a 10% threshold for a dichotomous result for presence or absence of significant ischaemia, there was moderate agreement between the methods .Thirty-eight patients [age 61 ± 8 ] underwent 2D high resolution (spatial resolution 1.2 mm2D high resolution and 3D whole heart myocardial perfusion stress CMR are comparable for detection of ischaemia. 2D high resolution gives higher values for myocardial ischaemic burden compared with 3D whole heart, suggesting that 2D high resolution is more sensitive for detection of ischaemia. Dynamic contrast-enhanced stress cardiovascular magnetic resonance (CMR) myocardial perfusion imaging has a high diagnostic accuracy for the detection of significant coronary artery disease (CAD)In a previous pilot study, 2D and 3D stress myocardial perfusion CMR were compared in patients with suspected CAD and demonstrated no overall significant bias although there was a large variation between measurements.Fifty-four patients with known or suspected CAD listed for an invasive coronary angiography (ICA) as part of routine clinical care were recruited. Patients were recruited either before or after ICA. For the latter, patients were only included if no revascularization was undertaken. Exclusion criteria were contraindication to MRI, previous coronary artery bypass graft (CABG) surgery, recent myocardial infarction (<6 months), unstable angina, or contraindication to adenosine or gadolinium contrast. Patients were advised to refrain from caffeine for 24 h prior to CMR. The study was approved by the National Research Ethics Service (15/NW/0778) with written informed consent obtained from all patients.CMR scans were performed on a 3-T MRI scanner  with dual-source parallel radiofrequency transmission technology and a 32-channel cardiac coil. Cine imaging for biventricular volumes and function was acquired with a balanced steady-state free precession (SSFP) cine sequence as recommended in guidelines.® EP, MEDRAD, Inc., USA). For both stress perfusions, patients were asked to breath hold at point of contrast arrival to the myocardium.Stress perfusion images were acquired following administration of intravenous adenosine at 140 µg/kg/min for a minimum of 3 min. An adequate stress response was determined by a decrease of 10 mmHg systolic blood pressure and/or a 10% increase in heart rate and typical symptoms and in cases in which there was a lack of response, the dose of adenosine was increased to 175 and 210 µg/kg/min.2; 10-fold k-t acceleration and 11 training profiles leading to a net acceleration of 7.0; typical acquisition window 192–230 ms, k-t PCA reconstruction; reconstructed to 12 contiguous slices with voxel size 2.3 mm × 2.3 mm × 5 mm3.For 3D whole heart myocardial perfusion imaging, the 3D volume was planned from the systolic frame of the four- and two-chamber cine with exclusion of the left ventricular outflow tract in the three-chamber cine. A 3D spoiled turbo gradient echo sequence was utilized, with typical parameters: TR/TE/flip angle 1.86 ms/0.7 ms/11°; saturation prepulse delay 150 ms; linear k-space encoding; 70% partial Fourier acquisition in two dimensions; typical field of view 350 mm × 350 mmk-space encoding; no partial Fourier acquisition; typical field of view 340 mm × 340 mm2; 5-fold k-t acceleration with 11 interleaved training profiles; typical acquisition window 100–134 ms, k-t PCA reconstruction; reconstructed to 3 non-contiguous slices with voxel size 1.2 mm × 1.2 mm × 8 mm3.For 2D high resolution imaging, three slices were planned from the base, mid, and apex using the ‘3 of 5’ approach, planned in systole. A turbo gradient echo sequence was utilized with typical parameters: TR/TE/flip angle 2.6 ms/0.9 ms/20°; saturation prepulse delay 120 ms; linear 2). LGE images were acquired in standard long-axis planes and also the entire short-axis views with 8-mm slice thickness and no slice gap.Late gadolinium-enhanced (LGE) imaging was performed 10 min following top up to 0.2 mmol/kg of gadolinium contrast from the second contrast injection. A T1-weighted segmented inversion recovery gradient echo was used . 3D whole heart and 2D high resolution myocardial perfusion images were anonymized and randomly presented to two experienced CMR readers with 7 and 6 years’ experience in CMR, respectively. Image quality was graded on a four-point scale .The presence and location of ischaemia were recorded using a 16-segment model. Myocardial ischaemia was visually quantified on DICOM images on a workstation using CVI-42 software version 5.12.2 . Perfusion defects were determined visually based on the presence of a subendocardial or transmural defect, which persisted for more than five dynamic phases, in areas that corresponded to a coronary artery territory, and exhibited delayed contrast enhancement compared to other myocardial segments in the same slice. The perfusion defect was contoured at peak stress perfusion and expressed as a percentage of the total myocardial volume in the perfusion images to derive the ‘total perfusion defect’. LGE was considered to be present if seen in long-axis and short-axis views. In order to quantify the amount of LGE, the endocardial and epicardial borders were outlined and then manual planimetry of areas of high signal intensity on a background of nulled myocardium was performed in each slice. Following summation of LGE areas, these were then multiplied by the slice thickness. This manual planimetry approach was employed, as there is no agreed consensus on method of LGE quantification in recent international guidelines.Patients underwent ICA at Guy’s and St Thomas’ Hospital, London. Quantitative coronary angiography (QCA) was performed retrospectively on X-ray coronary angiography images offline  by an experienced observer with more than 5 years’ experience in coronary angiography. Significant CAD was defined as vessel with FFR value of ≤0.80, and in those vessels in which FFR was not undertaken was defined by a coronary luminal stenosis >70% on QCA. The invasive measurement of ischaemic burden, the British Cardiovascular Intervention Society (BCIS) Duke’s Jeopardy score, was calculated as previously described.t-tests were used to compare means for parametric data, and Wilcoxon signed-rank test to compare image quality. Agreement of quantitative ischaemic burden and perfusion defect were analysed using intraclass correlation coefficients (ICCs) and compared using Wilcoxon signed-rank test and Bland and Altman analysis. For Bland and Altman analysis, in situations in which there was a non-random variation in differences (e.g. an increase in differences of measurements with increasing mean), a ratio transformation of values was performed.P < 0.05 were considered statistically significant.Statistical analyses were performed using SPSS Statistics 24 . Normality was assessed using Shapiro–Wilk tests. Results are expressed as mean ± standard deviation unless otherwise specified. Student Figure 1). All patients underwent ICA with a median of 9 days (interquartile range 3–16) of the CMR scan. Patient demographics are summarized in Table 1 and the distribution of CAD is provided in Table 2.Fifty-four eligible patients were considered for enrolment and 38 patients were recruited after exclusions (P = 0.09).Data from 6 of the initial 54 patients were not included in the study due to non-diagnostic image quality. Five of these related to 3D datasets that were degraded by motion that corrupted the reconstruction process. In the 38 diagnostic datasets, there was a trend for superior image quality with 2D high resolution median score (interquartile range) 3 (2–3) compared to 3D whole heart [2 (2–3)], although this was not statistically significant (P < 0.0001) and rate pressure product (RPP) increased from 8366 ± 1897 to 11695 ± 2644 mmHg min−1 (P < 0.0001) for rest and stress, respectively. For 3D whole heart stress, heart rate increased from 63 ± 10 to 91 ± 17 bpm (P < 0.0001) and RPP increased from 8463 ± 1608 to 11551 ± 2563 mmHg min−1 (P < 0.0001). There was no significant difference between rest heart rate, stress heart rate, blood pressure, or RPP between the two stress perfusions.For 2D high resolution stress, heart rate increased from 63 ± 10 to 90 ± 16 bpm (P < 0.0001). The median myocardial ischaemic burden (%) was significantly higher with 2D high resolution compared to 3D whole heart . The mean ratio difference between 2D high resolution vs. 3D whole heart was 1.28 ± 0.67 (95% limits of agreement −0.03 to 2.59).Ischaemia (defined by a perfusion defect in the absence of corresponding LGE or artefact) was present in 29/38 (76%) of patients with 3D whole heart and in 27/38 (71%) with 2D high resolution perfusion imaging. There was excellent agreement between 3D whole heart and 2D high resolution myocardial ischaemic burden with ICC 0.81 , single-vessel disease 1.20 ± 0.31 (95% limits of agreement 0.60–1.81), two-vessel disease 1.38 ± 0.54 (95% limits of agreement 0.33–2.42), and three-vessel disease 1.74 ± 0.71 (95% limits of agreement 0.36–3.13).Figure 2, there was a trend for higher myocardial ischaemic burden with 2D high resolution with greater ischaemic burden, particularly over 20%. The mean ratio of difference of myocardial ischaemic burden between 2D high resolution vs. 3D whole heart for patients was greater with patients with a mean ischaemic burden of >20% compared with <20% [1.50 ± 0.46 (95% limits of agreement 0.61–2.39) vs. 1.12 ± 0.76 (95% limits of agreement −0.37 to 2.61)]. When using a 10% threshold for a dichotomous result for presence or absence of significant ischaemia, there was moderate agreement between the two methods . There was an excellent intraobserver reproducibility for myocardial ischaemic burden with ICC 0.87 and CoV 4.5%.As shown in the Bland–Altman plot in P < 0.0001). The median myocardial perfusion defect (%) was significantly higher with 2D high resolution vs. 3D whole heart . The mean ratio difference between 2D high resolution vs. 3D whole heart was 1.20 ± 0.67 (95% limits of agreement −0.11 to 2.52). As with the findings for the myocardial ischaemic burden, and shown in Figure 3, there was a trend for a higher perfusion defect with 2D high resolution imaging with greater mean ischaemic burden, particularly over 20%.There was an excellent agreement between 3D whole heart and 2D high resolution myocardial ischaemic burden ICC = 0.95 .When using a 10% threshold for a dichotomous result for the presence or absence of significant amount of ischaemia, there was moderate agreement between the two methods (rs = 0.53), 3D perfusion defect (rs = 0.59), 2D ischaemic burden (rs = 0.55), and 2D perfusion defect (rs = 0.58).Compared with BCIS Duke’s jeopardy score derived from ICA for assessment of myocardial ischaemic burden, there was moderate correlation with 3D ischaemic burden . In one study (n = 45) that compared 3D whole heart myocardial perfusion CMR to SPECT, there was a small bias of 0.62% although wide limits of agreement.Previous studies have compared myocardial ischaemic burden between different imaging modalities (n = 35), there was a greater extent of ischaemia detected using high resolution compared to standard resolution 2D myocardial perfusion in patients with angiographically defined three-vessel disease.In another study (n = 651), total perfusion defect of whole heart was compared to three slices simulated from SPECT data.Undertaking two stress perfusions is challenging and has logistical challenges and therefore has limited most of the previous study sample sizes. In a retrospective simulation study (n = 27) similar to the current one, no significant difference in ischaemic burden was observed between 2D high resolution and 3D whole heart CMR, with a small overall bias −0.17% and also with wide 95% limits of agreement of −7.5 to 7.2%.In a previous study . Firstly, high resolution imaging accurately identifies the presence of subendocardial ischaemiaThere are several plausible explanations why 2D high resolution identified greater myocardial ischaemic burden compared to 3D myocardial perfusion imaging in our current study  compared to a 3D systolic acquisition of the apical slices. Thus, the higher myocardial ischaemia burden [ × 100] observed with 2D high resolution imaging may relate to the greater detection of subendocardial and transmural extent of ischaemia and a lower total denominator of the total myocardium volume imaged. Another aspect to consider is the point of acquisition in the cardiac cycle for 3D whole heart stress perfusion imaging (diastole vs. systole) which may impact on ischaemia assessment.Based on this study, we can estimate that using a 2D high resolution stress technique will provide an ∼28% greater myocardial ischaemic burden compared to 3D techniques. The magnitude of difference is important to understand, as different ischaemic burden values can be derived using different CMR methods. As to determine which technique is ultimately correct is challenging, as no formal comparison to a ground truth reference standard for myocardial ischaemia was undertaken in this study. Intuitively, 3D whole heart may considered as more accurate as it has full spatial coverage, but may miss important ischaemia that may be captured from a high resolution technique. Future studies may consider using techniques that allow whole heart spatial coverage and high in plane spatial resolution that may allow detection of subendocardial ischaemia and transmural extent through the entire left ventricle and potentially more accurately delineate the true extent of ischaemia. Such techniques are emergingk-t acceleration,,There are a number of limitations to acknowledge in this study. Firstly, while patients underwent both whole heart and high resolution perfusion imaging in the same scan session, the second contrast injection may have a higher baseline T1 value and potentially impact on the assessment of ischaemia. However, we attempted to minimize this effect by randomizing the order of acquisition of sequences for each patient. Secondly, the assessment of ischaemic burden was undertaken on visual analysis of a series of dynamic perfusion data, which may have introduced variability, although there was very good reproducibility of measurements. Thirdly, a substantial number of cases were excluded from the final analysis, primarily from 3D datasets due to poor image quality from corrupted image readout or poor breath holding. This is an important aspect to consider as despite initial clinical studies that held promise for 3D whole heart with Methods that use whole heart perfusion imaging combined with high resolution techniques may provide a more accurate assessment of ischaemia. With emerging methods for quantification of absolute myocardial blood flow and with 3D techniques,2D high resolution and 3D whole heart myocardial perfusion stress CMR are comparable for detection of ischaemia but 2D high resolution measures higher myocardial ischaemic burden compared to a 3D whole heart approach, suggesting that high resolution imaging is more sensitive for the detection of ischaemia. This has important implications for defining significant thresholds for ischaemia.Availability of data and material The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.


Increased systolic pulmonary arterial pressure (sPAP) could lead to the mechanical dysfunction and myocardial fibrosis of the right heart chambers. Echocardiographic strain analysis has not been adequately studied in patients with pulmonary hypertension (PH).A cross-sectional cohort of patients with suspected PH and echocardiographic strain evaluation was recruited. The cut-off values of peak tricuspid regurgitation velocity (TRV) with the low probability of PH (≤2.8 m/s), intermediate probability , and high probability of PH (2.9–3.4 m/s with other echo PH signs and >3.4 m/s) categories were studied by right ventricular and right atrial (RA) strain analysis in a sample of 236 patients.n = 12) demonstrated an association between increased sPAP before death and right ventricular and RA fibrosis.The results showed that 58 (56.9%) patients had low, 15 (14.7%) had intermediate, and 29 (28.4%) had a high probability of PH. We observed a negative association between right ventricular free wall strain (RV-FWS) and atrial global strain with sPAP. With the increase in PH severity, RA reservoir, conduit, and contraction (booster) strain values decreased. The identified cut-off values of strain parameters had an adequate ability to detect PH severity categories. In addition, the post-mortem biopsies of right heart chambers from subjects with known severe PH were analyzed to quantify myocardial fibrosis. Our sample of right heart biopsies (Mechanical dysfunction and fibrosis in the right chambers are associated with increased sPAP. Right ventricular and atrial strain could provide enhancement in the diagnosis and categorization of subjects with suspected PH. Conventional echocardiographic parameters used in daily clinical practice that evaluate RV systolic function include tricuspid annular plane systolic excursion (TAPSE), the maximum velocity of the tricuspid lateral annulus during systole or the S wave (S’), and RV fractional area change (RVFAC) . All theWe designed a cross-sectional study in which we recruited consecutive patients who were evaluated in the echocardiographic division from the Nuclear Cardiology Department (NCD) at the National Institute of Cardiology Ignacio Chavez, Mexico, between the period of June 2018 and December 2019. The patients attended our institution’s outpatient clinic due to dyspnea on exertion, fatigue, and dizziness and were sent for a transthoracic echocardiogram for further evaluation. All patients underwent conventional two-dimensional and Doppler transthoracic echocardiography, along with velocity vector imaging to assess the right heart chamber strain parameters. We excluded subjects with congenital heart diseases, prior myocardial infarction, sarcoidosis, mild or severe valvular disease, or subjects classified with unspecified cardiomyopathies. Patients with low echocardiographic image quality were excluded in the final analysis. We extracted our control group from the same patients who attended our institution’s outpatient clinic. The control group was defined by subjects who had normal pulmonary artery pressure values by echocardiographic measurement of peak tricuspid regurgitation velocity (TRV) (≤2.8 m/s) within our cohort sample. To assess the inter-rater reliability and reproducibility of echocardiographic sPAP parameters, 13 selected subjects from our first cohort were assessed at heart catheterization performed 10 days after the echocardiographic study. Written informed consent was obtained from all participants.We performed a complete conventional transthoracic echocardiogram with subjects in left lateral decubitus using a Siemens Acuson SC 2000  echocardiographic equipment with a phased array transducer. The right ventricular end-diastolic diameter was measured in the apical four-chamber view, below the tricuspid valve. The RV wall thickness was measured by 2D echocardiography in the subcostal four-chamber view. RA volume was obtained using a single-plane method of disks in the apical four-chamber view at ventricular end-systole, and it was indexed by body surface area (BSA). The measurements of RVFAC, TAPSE, tricuspid S-wave velocity, Tei index, E, A-wave velocities , E/A ratio, and tricuspid E/e′ ratio were obtained according to the guidelines of the American Society of Echocardiography and the European Association of Echocardiography , 10, 11.2 + right atrial pressure. RA pressure was estimated in the subcostal view according to inferior vena cava (IVC) size and collapsibility following a normal sniff: An IVC diameter <2.1 cm that collapsed >50% with a sniff suggested normal RA pressure of 3 mm Hg , whereas an IVC diameter >2.1 cm that collapsed <50% with a sniff suggested a high RA pressure of 15 mmHg . In scenarios in which the IVC diameter and collapse did not fit this paradigm, an intermediate value of 8 mmHg  might be used, or, preferably, other indices of RA pressure could be integrated to downgrade or upgrade to the standard or high values of RA pressure pressure . The echpressure .Strain assessment was performed offline using velocity vector imaging . All images analyzed were obtained at 50–80 frames/s at end expiration. The region of interest was traced with a point-and-click approach on the endocardium of the RV free wall at end-diastole in the RV-focused apical four-chamber view. A broader region of interest was subsequently generated and manually adjusted if necessary. The program automatically divided the RV free wall into three segments and performed the analysis of the deformation frame by frame. This process allowed an automated confirmation of the contour and generated deformation values. The peak strain values from the three free wall segments were averaged, and the mean value was taken as the right ventricular free wall strain (RV-FWS) , 11–13.For the right atrium (RA), the endocardial border was traced in the apical four-chamber view, excluding the appendage and the Eustachian valve from the RA cavity. RA longitudinal strain curves were generated throughout the cardiac cycle with R-R gating. The accuracy of the automated border tracking was verified and manually adjusted if needed. Tracking was repeated three times, and averages were used for analysis as reported in guidelines , 8, 11. To assess the intra- and inter-observer reproducibility of RA reservoir, conduit, and contractile strain, 13 randomly sampled analyses were repeated two times by the same observer and by a second observer without the knowledge of previous findings, respectively.The second cohort of 12 biopsies of the right heart chambers from the postmortem heart samples of patients diagnosed with severe PH were included. This cohort was created to evaluate the hazardous effect of increased sPAP on the development of fibrosis in the right heart chambers.The heart was photographed, the macroscopic characteristics were taken, and sections were made for histological study. Samples were taken from the RA and the right ventricular free walls. We took photographs of the longitudinal section from the atrium’s anterior wall, from the origin of the appendage to the tricuspid valve, and a transverse section of the ventricle in the middle portion of the free wall, covering the entire thickness of the wall.The samples were processed with the histological technique of “paraffin inclusion.” They were stained with the Masson technique to quantify the percentage of RA and right ventricular fibrous tissue, dividing the field of observation of the microscope into quarters. Two independent observers gave the percentage values, and a consensus value was obtained when there were differences. Microscopic photographs were taken of the most representative areas , 3.The study was carried out following the Declaration of Helsinki and was approved by the Ethics and Research Committee of the National Institute of Cardiology Ignacio Chavez. Reference number: PT-17-087.post hoc test was also assessed to evaluate the differences among groups.The frequency distribution of categorical variables is reported as frequencies and percentages. Data are presented as mean (SD) or median [interquartile range (IQR)] where appropriate. To compare the differences of echocardiographic parameters among PH categories, we performed a one-way ANOVA or Kruskal–Wallis test wherever it met assumptions of parametric tests or not, and Dunn’s R2 was reported to express the variability explained by both variables. As a second step, we adjusted these models for age, sex, and BSA as these variables could modify the relationship between RV-FWS and sPAP. As a secondary analysis, we evaluated the association of sPAP with the right heart chamber fibrosis of our second cohort sample, using the methods previously described.We performed a natural logarithmic transformation in variables with the non-parametric distribution. Afterward, we assessed the correlation of both RV-FWS and RA-GS with sPAP using Pearson’s correlation analysis to obtain the correlation coefficient with our transformed variables. To evaluate the prediction capacity of RV-FWS with sPAP, we performed polynomic adjusted linear regression analysis to assess the association between both parameters. The Optimal cut points” and evaluate the diagnostic test capacity, AUC, sensitivity, specificity, and positive and negative predictive values  to predict PH categories  analysis curves were generated and area under the curve (AUC) derived for RV and RA strain and compared with the Fraction of Shortening, TAPSE, TEI, which are commonly used echocardiographic parameters to evaluate right heart ventricular function. Furthermore, we sought to identify the optimal cut-off value of the strain parameters using the “Youden method” from the R package “tegories . Finallytegories . A valuer = 0.777  as well as with RA-GLS . RV-FWS and RA-GLS explained 22.2 and 18.3% of the variability of sPAP, respectively. These trends were sustained after adjusting for age, sex, and BSA. Interestingly, we observed that both parameters had a quadratic fit adjustment , but not with atrial fibrosis , which explains the 18.3 and 8.1% of the variability of right ventricular and atrial fibrosis, respectively , both RV-FWS and RA-GS showed an adequate AUC to identify the presence of PH and their respective severity categories. RA-GS outperformed other echocardiographic parameters to detect those patients with any degree of PH , while RV-FWS outperformed in those with the high probability of pulmonary hypertension  . RV-FWS In this study, we show the association of both right ventricular free wall and global right atrial strain with increased systolic pulmonary artery pressure. Moreover, we demonstrate that pulmonary arterial hypertension could be associated with the myocardial fibrosis of the right heart obtained with histopathological methods. These findings suggest that the association of increased sPAP values with overall ventricular deformation and fibrosis. Finally, we demonstrate that strain parameters contribute to the detection of PH and the assessment of PH severity in patients with a suspected probability of PH.via the Frank-Starling mechanism that progressively decreases as the disease advances. This may be more pronounced in the RV, as the chamber directly faces the increased afterload, before impairing the right atrium. The atrial function is altered as observed in the evaluation of the various atrial phases. Finally, the degree of fibrosis analyzed in the pathological specimens of a subset of patients with PH was associated with a prolonged decrease in ventricular function.The relationship between ventricular deformation and sPAP has been previously reported –18. A chWith the demonstration of fibrosis, usually an irreversible change, early detection, and the stratification of PH is critical. Our data demonstrate the clinical utility of RV-FWS and RA-GS as echocardiographic parameters that aid in this task. Strain parameters have been previously used to predict outcomes in congestive heart failure and myocardial infarction with similar results , 22, as n = 13), given by the invasive and selective criteria to perform this procedure in all studied population. Furthermore, given the cross-sectional design of our study, we did not assess the etiology of our cases. Nevertheless, according to the evidence published by the “Mexican Registry of Pulmonary Hypertension (REMEHIP),” approximately 43% of all patients with PH in our country had idiopathic PH (Our study has some limitations. Our patients were recruited at a referral hospital, which may represent a population bias in terms of disease prevalence and severity. Despite this, our population had a significant cohort without PH and had various degrees of pulmonary hypertension. We did not recruit an external cohort to define our control group. Instead, the control group was defined by subjects who had normal pulmonary arterial pressure within our same cohort. Moreover, there was, however, only a small number of patients with moderate PH, potentially affecting our ability to see significantly different measurements between the moderate and severe PH categories. Another potential limitation was the restricted number of patients submitted to cardiac catheterization (athic PH . AdditioIncreased pulmonary artery pressure is associated with the dysfunction of the right atrium and RV as shown by decreased RV and RA peak global longitudinal strain. We believe that this chronic dysfunction may be related to an eventual risk for fibrosis. The use of echocardiographic derived strain parameters in clinical practice could be a potential tool for detecting the presence and evaluating the probability of PH as estimated by sPAP. If validated, proposed cut-off values may improve the clinical staging of PH by including a non-invasive marker of dysfunction or fibrosis.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics and Research Committee of the National Institute of Cardiology Ignacio Chavez. Reference number: PT-17-087. The patients/participants provided their written informed consent to participate in this study.NE-Z, NA-V, and EA-R contributed to research idea and study design. RA-S, GC-C, AA-F, and DO-C contributed to data acquisition. NE-Z, NA-V, and EG contributed to data analysis/interpretation. NA-V and EG contributed to statistical analysis. NE-Z, NA-V, LR, EA-R, and NN contributed to manuscript drafting. NE-Z, NN, and LR contributed to supervision or mentorship. All authors contributed to important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Thirteen Yorkshire pigs submitted to three consecutive stages with two opposite interventions each: changes in afterload (phenylephrine/nitroprusside), preload (bleeding/reinfusion and fluid bolus), and contractility (esmolol/dobutamine). LV pressure–volume data were obtained with a conductance catheter. Segmental mechanical dyssynchrony was assessed by global, systolic, and diastolic dyssynchrony (DYS) and internal flow fraction (IFF). Late systolic LVMD was related to an impaired VAC, LVeff, and LVEF, whereas diastolic LVMD was associated with delayed LV relaxation (logistic tau), decreased LV peak filling rate, and increased atrial contribution to LV filling. The hemodynamic factors related to LVMD were contractility, afterload, and heart rate. However, the relationship between these factors differed throughout the cardiac cycle. LVMD plays a significant role in LV systolic and diastolic performance and is associated with hemodynamic factors and intraventricular conduction.Left ventricular mechanical dyssynchrony (LVMD) refers to the nonuniformity in mechanical contraction and relaxation timing in different ventricular segments. We aimed to determine the relationship between LVMD and LV performance, as assessed by ventriculo‐arterial coupling (VAC), LV mechanical efficiency (LV Hemodynamic and electrical factors associated with left ventricular mechanical dyssynchrony during the cardiac cycle and their relationship with the systolic and diastolic ventricular function. Left ventricular mechanical dyssynchrony (LVMD), therefore, refers to the nonuniformity in mechanical contraction and relaxation between different ventricular segments  of 5.6 ± 0.7 (mean ± SD) months old, weighing 82 ± 5 kg. Animals were maintained in a temperature and humidity‐controlled rooms with a 12‐hour light–dark cycle and standard chow and tap water ad libitum. The animals were premedicated with an intramuscular combination of telazol (4.4 mg kg−1), ketamine (2.2 mg kg−1), and xylazine (1.1 mg kg−1). They were orally intubated, and their lungs were mechanically ventilated in volume‐controlled mode using a fraction of inspired oxygen of 0.6, an inspiratory to expiratory ratio of 1:2.5, tidal volume of 10 mL/kg plus 100 mL compensation for dead space, and a respiratory rate adjusted to maintain a PaCO2 of between 4.5 and 6 kPa. General anesthesia was maintained by 1%–2% isoflurane and a mixture of oxygen, air, and/or nitrous oxide without a neuromuscular blocking agent. Fluid maintenance was provided by an intravenous infusion of Ringer's lactate solution (4 mL kg−1 h−1). Rectal temperature was monitored and kept between 38 and 40°C using a heating pad. The depth of anesthesia was evaluated every 15 min by inspecting the jaw tone and the toe pinch response. Animals were sacrificed at the end of the study with a lethal dose of sodium pentobarbital (90 mg kg−1).Experiments were performed in 13 Yorkshire crossbred female domestic pigs , and connected to a pressure–volume signal processor . The catheter was inserted through the left external carotid artery and positioned along the LV long axis. Correct placement was confirmed by fluoroscopy and the inspection of the morphology of the individual segmental LV pressure–volume loops. In the swine heart, five LV segments defined for each pair of electrodes from third to eighth typically cover the LV cavity from base to apex. The remaining electrodes were excluded for the pressure–volume analysis. A fluid‐filled pulmonary artery catheter  was inserted percutaneously through the right internal jugular vein to the pulmonary artery.The volume signal was calibrated using the thermodilution method via right‐heart catheterization. The average value of 3–5 thermodilution ice‐cold saline boluses randomly injected during the respiratory cycle was used to determine cardiac output (CO). Correction for parallel conductance  was performed with 10 mL boluses of 5% hypertonic saline through the distal port of the pulmonary artery catheter  = P(t)/V(t) − V0, where V0 is volume‐axis intercept or the LV unstressed volume. End‐systole was defined at the maximum value of the LV elastance , stroke volume (SV), CO, LV end‐diastolic volume (EDV), LV end‐systolic volume (ESV), LV end‐diastolic pressure (EDP), and LVEF calculated from five beats in steady‐state conditions during a respiratory pause before the IVC occlusion. Effective arterial elastance (Ea = Pes/SV) was used as a lumped parameter of LV afterload  was calculated using the logistic method  as  Mirsky, . LV rela2.5V0). The ratio of SW/PVA represents the LV mechanical efficiency (LVeff) of transferring the total mechanical energy into SW  was defined as the ratio of Ea to Ees , which does not consider the loss in pulmonary veins, was calculated by subtracting the LV volume at the onset of atrial systole to EDV. Similarly, the atrial systolic pressure gradient was calculated as the difference between EDP and the pressure at the beginning of atrial systole. Atrial power was determined as the product of SVatria and atrial systolic pressure gradient divided by the duration of atrial systole, expressed in watts. The contribution of the atrial contraction to the LV preload and SV was calculated as SVatria/EDV and SVatria/SV, respectively, and expressed as a percentage.The onset of the atrial systole was determined by analyzing the LV volume curve at the point where the ventricular volume increases before end‐diastole, which usually occurs at the last zero‐crossing of the first derivative of LV volume Figure . Effecti2.7Vseg) obtained from the conductance catheter  and the internal flow fraction (IFF) from the ventricular segmental volumes (Vseg) changes and the absolute total volume  change:Internal flow (IF) quantifies the segment‐to‐segment blood volume shift produced by nonuniform contraction and filling, which results in an ineffective filling or ejection  and dividing by the absolute effective flow time integral:dP/dtmax) and late systole (from dP/dtmax to Emax), and the diastole into early (from Emax to PFR) and late diastole (from PFR to R wave)  was calculated by integrating IF over the cardiac cycle duration (2.8−1 min−1) to increase MAP by 40% mmHg from baseline, and then, they were allowed to recover. Then, they were treated with sodium nitroprusside (100–200 mg kg−1 min−1) to decrease MAP by 40% from baseline but not below 50 mmHg to allow an adequate hemodynamic tolerance during the IVC occlusions, followed by recovery to baseline status. Subsequently, for preload interventions, the animals were submitted to stepwise bleeding of 12 mL kg−1 (50 mL min−1), and the blood was stored in a heparinized sterile bag. Then, the blood was reinfused at the same rate, and an additional fluid bolus of 10 mL kg−1 of a colloid was infused in 5 min. After the fluid administration, the contractility interventions followed: an esmolol infusion was started at 50 μg kg−1 min−1 and increased until reducing LV dP/dtmax by 50% from its previous value, with a limit dose of 200 μg kg−1 min−1. Then, the esmolol infusion was stopped and, after a recovery period, a dobutamine infusion (5 μg kg−1 min−1) was used to increase LV dP/dtmax by >50%. LV PV loops and arterial pressure waveforms were obtained at each baseline and after each intervention. Animals were euthanized at the end of the study with an intravenous dose of sodium pentobarbital (90 mg kg−1).Animals were initially resuscitated with colloid boluses  until there was no further increase in CO. Then, they were allowed to stabilize for at least 10 min (heart rate and MAP variation <5%). The study protocol consisted of three consecutive stages with two opposite interventions: changes in afterload (phenylephrine and sodium nitroprusside), preload (bleeding and fluid bolus), and contractility (esmolol and dobutamine). The experiment started with the afterload interventions: animals received a phenylephrine infusion  and the Kenward‐Roger degrees of freedom adjustment, using individual animals as a subject for random factors and experimental stages as repeated measurements. A p‐value <0.05 was considered statistically significant. The authors had full access to and took full responsibility for the integrity of the data. All authors have read and agreed to the manuscript as written.Data are expressed as means ± standard deviation. Differences during interventions were assessed by a paired 33.1dPdtmax by 46 ± 18%, while dobutamine increased by 88 ± 22%.A detailed description of the hemodynamic variables during afterload, preload, and contractility interventions is shown in Tables 3.2eff decreased with phenylephrine (relative decrease: 8 ± 8%), fluid bolus (11 ± 10%), and esmolol (27 ± 14%), and it improved with nitroprusside (relative increase: 15 ± 14%), bleeding (14 ± 11%), and dobutamine (21 ± 10%). LV relaxation (τ) was delayed by 4 ± 2 ms with phenylephrine and 6 ± 4 ms with esmolol and reduced with dobutamine by 3 ± 2 ms. Preload changes did not affect LV relaxation. LV stiffness constant (β) decreased with bleeding and increased with fluid loading and esmolol  and 0.969 (95% CI: 0.963 to 0.975) for the EDPVR. Whereas phenylephrine increased VAC because of a more noticeable increase in Ea, nitroprusside and bleeding improved VAC by a selective decrease in Ea. Fluid loading increased VAC by reducing Ees, whereas esmolol impaired VAC by increasing Ea without any significant change in Ees. However, the ESV increased with esmolol, reflecting a rightward shift of the LV ESPVR. Dobutamine improved VAC by enhancing Ees without changes in Ea. LVl Tables .3.3Baseline DYS and IFF were 14 ± 2% and 6 ± 2%, respectively. The temporal distribution of the segmental LVMD throughout the cardiac cycle in baseline conditions is shown in Figure p = 0.017). The contribution of systolic and diastolic dyssynchrony to the global DYS was 46.5% (95% CI: 45.4% to 47.7%) and 60.2% (95% CI: 58.4% to 62%), respectively. The relationship between global DYS and IFF was strong  and described by the exponential function IFF = 0.4839 + 0.001777·DYS + 0.02934·DYS2, which implies that ineffective LV volume shifting increases faster at higher DYS levels.Systolic DYS was only partially related to diastolic DYS , reduced PFR, and higher LV dP/dtmin  .Systolic DYS and IFF were related to VAC, LVEF Table , particuEF Table . The hige) Table . A 10% i3.5The contribution of atrial systole to LV preload remained unchanged along the different experimental stages but was associated with significant atrial power and duration changes Table . The con3.6We assessed in a univariate and multivariate analysis the potential hemodynamic and electrical factors influencing LVMD Table . Reduced4This study assessed left intraventricular longitudinal mechanical dyssynchrony using the conductance catheter technique in an intact cardiovascular system under different loading and contractile conditions. Our results are in agreement with early observations by Brutsaert about the role of mechanical dyssynchrony as a physiological modulator of normal LV function  and lower than the values reported in patients with heart failure  on LVMD. During systole, Ees, Ea, and QRS duration were the main factors associated with LVMD, whereas during diastole, only heart rate and Ea were related to LVMD.In our study, LV afterload played a significant role in systolic and diastolic LVMD. Hayashida et al.  showed tThe effects of heart rate in LVMD have been addressed explicitly by Kurita et al. . These aWe have found a significant relationship between LVMD and EDV in the univariate analysis but not in the multivariate one. In an early work, Gillebert and Lew  observed4.5Our results showed that LVMD is a dynamic phenomenon that affects LV performance and is influenced by the relative contribution of hemodynamic factors and the electrical intraventricular conduction, expressed as the QRS duration. Consequently, the presence of pathological LVMD could be analyzed from this perspective  . Committee on Care and Use of Laboratory Animals). The Test Facility is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, International (AAALACi) and registered with the US Department of Agriculture for conducting animal research. This manuscript adheres to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines  at the Edwards Research Center approved the study protocol (reference number: EW2017‐31), and all procedures were performed following the USDA Animal Welfare Act regulations (AWArs). All animals received humane care in compliance with the US National Institutes of Health Data S1Click here for additional data file.