The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e′), and left ventricular end-diastolic pressure(LVEDP) have been shown to be correlated at rest, provided that patients are not on positive inotropic drugs. Data concerning the latter correlation during exercise stress are conflicting. Therefore, we investigated if use of negative inotropic drugs (NID), impacts the accuracy of E/e′ as a surrogate for LVEDP during low-level exercise. An exercise(50 watts) during cardiac invasive hemodynamic monitoring and an exercise echocardiography were performed prospectively within 24 hours in 54 patients  with preserved LV Ejection-Fraction. Before exercise, the patients had scattered LVEDP (13.8 ± 5.8 mmHg) and septal E/e′ (8.7 ± 2.7). Half of them were on NID, mainly betablockers(n = 26). The correlation between septal-E/e′ and LVEDP was low for examinations performed at rest  with no significant impact of NID. For measurements performed at 50 Watts, NID had a significant impact on the association between septal-E/e′50 watts and LVEDP50 watts . Correlation between septal-E/e′50 watts and LVEDP50 watts persisted in patients on NID  while it disappeared in the group of patients with no NID . NID use is an important confounding factor to take into consideration when assessing exercise LVFP using stress E/e′ in patients with preserved LVEF. However, the invasive nature of this exploration limits its dissemination and echocardiography has been proposed as an alternative method for LVFP monitoring4. The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e′) is currently the most widely used Doppler ultrasound parameter to diagnose elevation of LVFP. Several studies have shown a good correlation between E/e′ and LVFP at rest, in patients with chronic heart failure, either with preserved or altered left ventricular ejection fraction (LVEF)8. However, recent data have challenged the validity of this parameter10. In particular, the use of E/e′ during exercise is a matter of debate14. Stress E/e′ has first been validated in a study of small sample size, in patients with heterogeneous LVEF almost all treated with beta-blockers3. However, conflicting results have been reported in other studies assessing E/e′ to evaluate exercise LVFP in various populations with preserved LVEF, including untreated healthy subjects15.Cardiac catheterization has demonstrated its usefulness for the diagnosis of early stage of heart failure with preserved ejection fraction (HFpEF), which is characterized by exercise-induced abnormal left ventricular filling pressure (LVFP) despite normal resting values16. Nagueh et al., suggested using the ratio of E to tissue-Doppler mitral annular early diastolic velocity, E/e′, as a surrogate for invasive LVFP. E was estimated to be corrected for the influence of LV relaxation by e′, which was considered a preload-independent index of LV relaxation17. Positive and negative inotropic drugs have been shown to modify LV relaxation20 and also affect e′ preload-independence in experimental conditions18. In a canine model, when LV relaxation was impaired by beta-blockers use (Tau constant > 65 msec), e′ was preload-independent. In contrast, when dobutamine was used, LV relaxation was enhanced (Tau constant < 50 msec) and e′ lost its preload-independence18. Confirming these non-clinical data, our group and others reported that positive inotropic agents severely impaired the correlation between E/e′ and invasive evaluation of LVFP in patients with decompensated end-stage systolic heart failure22 while this correlation was good in the same type of patients treated by beta-blockers6. We therefore hypothesized that exercise, by releasing endogenous catecholamine23, also alters the correlation between E/e′ and LVFP during stress echocardiography unless patients are concomitantly treated with negative inotropic drugs (NID) such as beta-blockers. In order to test this hypothesis, the aim of this study was to assess the impact of NID use on accuracy of stress E/e′ as a surrogate for exercise LVFP using a direct invasive measurement as the reference method in patients at high risk of heart failure with preserved ejection fraction (HFpEF).Pulsed-Doppler early diastolic transmitral peak flow velocity (E) is considered to be a composite parameter mainly depending on LVFP and LV relaxationAmong the 60 patients initially enrolled in the study, 6 patients had incomplete data during exercise ; leaving 54 patients for final analysis. Patients were mainly male 81%) with a mean age of 62 ± 9 years. Sixty-one, 28 and 39% of patients had hypertension, diabetes or history of coronaropathy, respectively. Twenty-seven patients (50%) were treated by a NID, mainly a beta-blocker (n = 26), whose type and doses are detailed in Table % with a An example of data acquisition is presented in Fig. The median time between echocardiography and catheterization was 4 hours 49 minutes. There were no significant differences in baseline echocardiographic data according to NID use or not Table . No patiat rest/25/50 watts as a function of septal E/e′ value, NID use or not, presence of known coronaropathy, heart rate, and indexed left ventricular mass. Septal E/e′ rather than lateral E/e′ was chosen since correlations between septal E/e′ and LVEDP were stronger at rest, 25 and 50 watts  was performed for determination of LVEDP at rest, was significantly  associated with LVEDP at rest without influence of NID. During exercise, at 25 and 50 watts, only septal E/e′at 25/50 Watts  and NID use or not  were significantly (p ≤ 0.01) associated with LVEDP at 25/50 Watts. The other parameters tested were not significantly associated to LVEDP value at 25/50 Watts.At rest, only septal E/e′at 25 Watts and LVEDP at 25 Watts was slightly better in NID group  compared to no NID group . At 50 watts, differences in the correlation between septal E/e′ at 50 Watts and LVEDP at 50 Watts were further improved with good correlation in patients on NID  while it disappeared  in the no NID group  and 0.72 (p ≤ 0.05), respectively. In the group of patients off NID (n = 27), ROC curves analysis for prediction of abnormal stress LVEDP (>16mmHg and ≥25mmHg) from septal E/e′ at 50 Watts were not significant .In the group of patients on NID (n = 27), ROC curves analysis for prediction of abnormal stress LVEDP (>16mmHg and ≥25mmHg) from septal E/e′ In this prospective study, we evaluated the impact of NID on the accuracy of Doppler echocardiography to assess LVFP in patients with preserved LVEF at risk of developing abnormal exercise LVFP increase at low workload levels as the reflection of early stage HFpEF. We found that NID use had no influence on the association of septal E/e′ with LVEDP at rest. During exercise, the correlation between septal E/e′ and LVEDP persisted only if patients were on NID. These results may explain the conflicting data about the validity of stress E/e′ for the assessment of exercise LVFP in patients with preserved LVEF. This finding may have a clinical significance particularly when considering that NID are frequently withdrawn in routine practice before a stress test.26. Later, it was found that this correlation between E/e′ and LVFP was abolished by catecholamine use both in patients with and without cardiac systolic dysfunction28. In recent years, concerns have been raised about the reliability of echocardiography for estimating LVFP during exercise. A small sample size study found a good correlation between LVEDP and E/e′ in patients with variable LVEF, mostly on beta-blockers3. This finding was also confirmed in another study in patients with advanced HFpEF mostly on betablockers14. In contrast, several recent studies reported the absence of association between LVEDP and E/e′ or their variations during exercise, in untreated patients with preserved LVEF13. In our relatively large and well phenotyped cohort, we found that NID use influences the association between stress E/e′ and the direct invasive measure of LV diastolic pressure as the reference method. Thus, our results give new insight concerning previous discordant results. Moreover, our study emphasizes the importance of NID maintenance for stress echocardiography when performed for diagnosis of HFpEF. Recommendations concerning beta-blockers management before stress echocardiography are lacking in the recently updated guidelines for the evaluation of left ventricular diastolic function by echocardiography4.Several studies found that E/e′ was a better surrogate for LVFP at rest in patients with low LVEF on beta-blockers compared to patients with preserved LVEF20. By contrast, e′ variation is little affected by filling pressure and has been validated as a preload-independent index of LV relaxation17 in cases of Tau lengthening, such as that associated with left ventricular systolic dysfunction29 or with NID use such as beta-blockers18. This may explain why use of E/e′ as a surrogate of LVFP has mostly been validated in patients with structural heart diseases, in particular LV systolic dysfunction on beta-blockers26 and not in patients on positive inotropic drugs or during exercise. In fact, exercise is responsible of endogenous release of catecholamine, i.e. positive inotropes23. Therefore, our findings in humans confirm these preclinical findings in canine models where use of inotropes impaired the association between E/e′ and hemodynamic evaluation of LVFP, as opposed to beta-blockers, which improved it20.It has been shown in animal models that positive inotropic drugs improve LV relaxation (shortening constant of relaxation Tau) and increase the dependency of e′ on load variationsHeart catheterization and trans-thoracic echocardiography were not performed at exactly the same time and this may have contributed to decrease the magnitude of correlations between LVEDP and E/e′. However, good quality echocardiographic exams are difficult to obtain in catheterization laboratories and can lead to acquisitions of poor quality. Moreover, this methodological choice ensured that echocardiographic acquisitions and analyses of the data were made blindly of invasive measurements. The patients were investigated using exactly the same exercise protocol and without any modification of their drug treatments.In patients treated with NID, treatment strategies were highly heterogeneous, with various doses and types of NID used, potentially leading to different effects on heart and vascular function. Too few patients were included in this study for additional multivariable analyses to be performed to assess any influence of type and dose of NID. Of note, in current clinical practice, strictly identical echocardiographic parameters are used for the estimation of LVFP in patients with different type and doses of NID or either without NID.Since the non-invasive diagnosis of early stage HFpEF remains a major clinical challenge, we decided to focus our investigations on patients with preserved LVEF. The assessment of the influence of NID on stress E/e′ diagnostic accuracy in patients with altered LVEF deserves further investigations. In these latter patients, a focus on several comprehensive evaluations after careful beta-blocker dose up-titration is needed, seeking for dose-effect impact of NID on the relationship between E/e′ and LVFP.30. The study protocol and all methods applied were approved by the Committee for the Protection of Human Subjects of Pitié-Salpétière  and prior written informed consent was obtained from all subjects after being fully informed regarding the nature and risks of the study. We did the study in accordance with the principles of the international conference on harmonization guidelines on good clinical practice and the world medical association declaration of Helsinki.This study was ancillary to the PREFFORT study (NCT01714752)30. Briefly, we prospectively enrolled 60 patients, among those admitted to the Pitié-Salpêtrière hospital in Paris, France, between 12/2012 and 07/2013, for clinically indicated left heart catheterization. Included patients had to undergo invasive and non-invasive assessments of LVFP within 24 hours, without change to their medications during that interval.The methods was previously described in details elsewhereAll included patients fulfilled the following criteria: (1) in sinus rhythm with LVEF >50%; (2) without any significant valve disease, hypertrophic cardiomyopathy, heart transplantation, atrial fibrillation, severe mitral annular calcification, LV thrombus, severe renal failure and (3) without any acute coronary syndrome in the previous 3 months or angiographic diagnosis of a stenosis requiring a percutaneous coronary intervention.2. Thus, the patients referred for coronary angiography were also at high risk of developing abnormal exercise LVFP as the reflection of early stage HFpEF2.The risk factors of coronary artery disease, especially age, hypertension and diabetes, are also recognized as risk factors of HFpEFOn admission, demographic data , baseline clinical data, type of NID  and of other current treatments were collected prospectively. The type and dose of NID were left at the discretion of the treating physician.31.After realization of the coronary angiography for diagnostic purpose, a fluid-filled pigtail catheter introduced through the radial artery was positioned in the mid-LV cavity using fluoroscopy, with the patient in the supine position. This catheter was connected to a strain-gauge pressure transducer positioned at right atrium level and zeroed before measurement. LV pressure tracings were recorded at baseline and during exercise. Measurements were made off-line, blindly from echocardiographic and clinical data by two experienced physicians. LVEDP measurement was averaged over five cardiac cycles. A hemodynamic LV end-diastolic pressure (LVEDP) ≤16 mmHg was defined as normal at rest. An increase of LVEDP >16 mmHg (moderate), and to a further extent ≥25 mmHg (important), was considered abnormal during stressTransthoracic echocardiography was performed using a Vivid 9  by an experienced physician blinded to clinical and invasive data. Images were transferred to a workstation equipped with the Echopac PC software version 12.0 . All examinations were analyzed off-line. All measurements were averaged over 3 to 6 cardiac cycles.32: LV internal diameter, inter-ventricular septal and posterior wall thicknesses at end diastole from M-mode. LV mass was derived. Left atrial maximal volume was measured in 2-dimensional mode at the end of ventricular systole just before opening of the mitral valve by biplane Simpson method from apical four and two-chamber views. LV volumes and LVEF were measured using the biplane Simpson method. When appropriate, preceding measures were indexed to body surface area. Trans-mitral E and A were determined by pulsed-Doppler echography. Using tissue-Doppler data, we acquired e′ in early diastole, in spectral mode, for both the basal septal and lateral segments, using the four-chamber apical view  and then, in echocardiography laboratory using ERG 911 L/LS ergometer . Patients pedaled (50–60 cycles/minute) in the supine position, beginning at a workload of 25 Watts for 3 minutes, then at 50 Watts for another 3 minutes. Heart rate, blood pressure, invasive hemodynamic and non-invasive echocardiographic data were collected at baseline and during the last minute of each level of exercise, i.e. 25 and 50 Watts , as appropriate. Multiple regression analysis (ANCOVA) was used to study association between LVEDP and E/e′, considering other covariates such as NID use , at rest, 25 and 50 Watts. The choice of using septal or lateral E/e′ for these analyses was determined by the strength of their respective correlation with LVEDP. Receiver-operator characteristics (ROC) curves were plotted to determine diagnostic properties of E/e′ value to predict exercise LVEDP >16 mmHg and ≥25 mmHg, as a function of NID use .For quantitative variables, mean and standard deviations (SD) were calculated. Discrete variables are presented as percentages. Continuous variables were compared with unpaired NID use is an important confounding factor to be taken into account when assessing exercise LVFP using stress E/e′ in patients with preserved LVEF.


Patients with peripartum cardiomyopathy (PPCM) often express a desire to conceive again, and the risk of relapse in future pregnancies should be disclosed. No consensus is available that can determine that risk. Adequate contractile reserve, evidenced by a stress echocardiogram (exercise or dobutamine), can identify those with lower relapse risk. Peripartum cardiomyopathy (PPCM) is myocardial disease of pregnancy in which heart failure develops during the last month of pregnancy or up to 5 months postdelivery with no identified cause. Patients might recover, but there is a risk of recurrence with subsequent pregnancies. Risk factors for recurrence are diverse and include clinical, biochemical, and echocardiographic variables. Dobutamine stress echocardiography (DSE) is reported in the literature to verify the recovery of the myocardium contractile reserve. We report two cases in which PPCM patients with recovered left ventricle (LV) function became pregnant again with no recurrence of their disease. These two females had a normal contractile reserve of LV with DSE prior to pregnancy, rendering them at low risk for recurrence.A 21‐year‐old primigravida was diagnosed with PPCM after child birth. She was found to be short of breath 1 day postcesarean section delivery. Her pregnancy was uneventful, and she was not known to have any medical illnesses. She was hypotensive with a blood pressure (BP) of 90/60 mmHg and a heart rate of 140 beats per minute (bpm). She deteriorated rapidly and required endotracheal intubation, mechanical ventilation, and inotropic support in form of dopamine and dobutamine infusions. Despite the initial course, she recovered and was discharged home after optimization of her antifailure medications. Her medication regimen included B blocker (Bisoprolol), angiotensin converting enzyme inhibitors ACEi (Ramipril), and mineralocorticoid receptor blockers MRA (Spironolactone) that were titrated to maximum tolerated doses. Her six‐month echocardiography study showed a normalization of LV systolic function. One year later, she expressed her wish to become pregnant again. Her medications were tapered down with withdrawal of one medication at 2 weeks interval . To stratify her risk of PPCM recurrence, we elected to perform a DSE test to assess her myocardial recovery and contractile reserve.A 22‐year‐old primigravida was diagnosed with PPCM after delivery of her child. She presented to the labor ward with shortness of breath and an elevated blood pressure of 180/110 mmHg. Her past medical history was unremarkable. She was initially managed as having pre‐eclampsia, but despite adequate blood pressure control and the delivery of her baby through cesarean section, she deteriorated further and required intubation and mechanical ventilation. Nitroglycerin infusion was used to control her blood pressure, and loop diuretic was added as decongestive therapy. B blockers (carvidelol), angiotensin receptor blockers ARB , and spironolactone were used and up titrated as tolerated. She progressively improved and was discharged after 10 days. Her LV systolic function has normalized by 6 months postdischarge. After 2 years, she and her husband were eager to have a second baby and wanted to know if it was going to be safe for her. We tapered down the medications with same scheme of previous patient. We performed DSE to judge the recovery of her myocardium and assess the contractile reserve after stopping all antifailure medications.Table The patient became pregnant again 4 months after her DSE. Serial follow‐up visits during her pregnancy revealed no evidence of symptoms suggestive of a PPCM recurrence. Echocardiography was repeated during her second trimester and again prior to delivery, and normal LV systolic function was found Table . Her delThe patient decided to become pregnant again after she was stratified as low risk for recurrence of PPCM. She had follow‐up visits during her pregnancy with no evidence of heart failure symptoms. Her LV function was normal on echocardiography studies performed during her second trimester and prior to delivery Table . She gavWe presented the clinical history of two females who recovered from PPCM and completed successful pregnancies after a normal DSE. How we estimate the risk of PPCM relapse in future pregnancies is a vexing question. Different markers have been identified that can negatively or positively predict myocardial recovery. Their variability reflects the ambiguity of PPCM etiology. These factors are diverse from being clinical, hormonal, or imaging modalities. Some examples include race, comorbidities, relaxin level, pro‐BNP titer, LV dimension in diastole, and global longitudinal strain Conflicting opinions exist as to whether dobutamine or exercise stress echocardiogram would be a best surrogate of the hemodynamics during pregnancy. PPCM is a heart failure syndrome confined to late pregnancy and the postpartum period RAB: was a cardiology consultant involved in the case management, literature review, discussion writing, and final review of cases submitted. AH: was a cardiology resident involved in the case management, literature review, and case history writing. ZA: was a gynecology consultant involved in the case management, and literature review.None declared.


This was accompanied by an increase of transmural differences in wall stress. These results suggest that the transmural differences in EMD and MSV play an important role in physiological contractility of LV by synchronising the contraction of individual layers of ventricular wall during the systole. Reduction or enhancement of these differences may therefore impair the function of LV and contribute to heart failure.Recent studies have shown that left ventricle (LV) exhibits considerable transmural differences in active mechanical properties induced by transmural differences in electrical activity, excitation-contraction coupling, and contractile properties of individual myocytes. It was shown that the time between electrical and mechanical activation of myocytes  decreases from subendocardium to subepicardium and, on the contrary, the myocyte shortening velocity (MSV) increases in the same direction. To investigate the physiological importance of this inhomogeneity, we developed a new finite element model of LV incorporating the observed transmural gradients in EMD and MSV. Comparative simulations with the model showed that when EMD or MSV or both were set constant across the LV wall, the LV contractility during isovolumic contraction (IVC) decreased significantly (( Myocardial infarction and heart failure belong to leading causes of death in the Western world. Both the clinical practice and laboratory research have shown that the mechanical performance of left ventricle (LV) is one of the most important factors that affect the pump function of the heart. Thus, understanding the processes underlying the physiological and pathophysiological function of LV is unavoidable for efficient treatment of reduced LV contractility. Computational modelling has been proposed and actively pursued as a tool for accelerating research in cardiac biomechanics. Up to now, many attempts were done to describe mechanical properties of the heart and to simulate their impact on cardiovascular hemodynamics under health and disease (for latest reviews see –3).One of the favourite approaches enabling simulation of the effect of electromechanical properties of cardiac muscle on development of tension in LV wall and intraventricular pressure during heart contraction is based on three-dimensional finite element (FE) models e.g., –11). To . To 11])In 2004, Cordeiro et al.  showed tTo simulate the ventricular contraction, a three-dimensional FE model was built using commercial FE software ANSYS®. Since the anatomical realism is not crucial for the problem addressed in this study, the model was based on a simplified geometry. The inner cavity and the outer surface of the ventricle are approximated by ellipsoids with the same axes of symmetry, truncated by a plane perpendicular to their major axis mimicking the LV basal plane. The dimensions were set according to literature see  to definThe myocardial wall was discretized with 6048 quadratic hexahedral solid elements arranged in 7 layers. To mimic the active contraction of the myocytes, an additional reinforcing element in the form of a membrane parallel to both LV surfaces was embedded within each solid element. This membrane exhibits a unidirectional stiffness only to model the fibres aligned in a given direction. The angle of fibres against the circumferential direction (helix angle) varies linearly across the 7 layers from +60° in the inner  layer to −60° in the outer  layer , 21. Theai and bj are stress-like material parameters, I1 is the first invariant of right Cauchy-Green deformation tensor describing the isotropic part of deformation, and I4 is (pseudo) invariant of the right Cauchy-Green deformation tensor representing squared stretches in the fibre directions.To describe the passive mechanical behaviour of myocardium, an incompressible transversely isotropic hyperelastic model was used. The preferred direction of the model representing the direction of muscle fibres was set for each solid element individually following the same rule as mentioned above for the reinforcing elements. The model was defined by a polynomial strain energy density function having the formhttp://www.hyperfit.wz.cz) the following values were obtained: a1 = 0,347 kPa, a2 = 13,438 kPa, a3 = 48,846 kPa, b1 = 0,436 kPa, and b2 = 27,692 kPa. Since the passive response of myocardium is rate-dependent (effect of viscoelasticity), we utilized the results from equibiaxial tests performed at different testing speeds as well as from relaxation tests [The material parameters were obtained as the best fit of different biaxial tests of myocardium published by Sommer et al. ; using oon tests  and estiσ, ε, and E0 = 200 kPa are Cauchy stress, logarithmic strain, and initial Young's modulus, respectively. Due to limitations of ANSYS program, the above relation was incorporated into the model using a concept of multilinear elasticity with zero compression stiffness.As mentioned above, active contraction was incorporated into the model through reinforcing elements oriented in the local directions of myocytes in LV myocardium. To simulate heterogeneous time-dependent unidirectional contraction of myocytes, a simple approach based on prescribing time-dependent (negative) thermal strain in the fibre direction was used. A coefficient of thermal expansion was prescribed and the time course of contraction was governed by a gradual decrease in fictitious temperature . The unidirectional stress-strain relation for activated myocytes was estimated from the observed linear relation between force and length in fully contracted isolated cardiomyocytes. This relationship was independent of the mode of contraction and initial sarcomere length  and confIn each simulation, the onset of contraction was calculated for each contractile element individually taking into account the time course of electrical activation of LV myocardium and the transmural differences in EMD. The electrical activation was assumed to start simultaneously on the whole endocardial surface and to spread towards the epicardial surface with the velocity of 47 cm/s , 26. TheAs exact measurements of EMD and MSV across the wall of human LV are missing we implemented these features in our model on the basis of measurements from dog hearts published by Cordeiro et al. . They shThe time course of contraction max, the model generates a value of 237.3 kPa/s (1780 mm Hg/s) that falls into the range of physiological values reported in the literature [Behaviour of the control model is illustrated in terature  and is aterature . These vdp/dt)max was only slightly changed (from 1780 mm Hg/s in control to 1740 mm Hg/s at constant EMD). An analysis of wall tension development during IVC under constant EMD revealed that this effect arose from a delay in the onset of contraction in the midmyocardial and subepicardial layers max from 1780 mm Hg/s (control) to 1110 mm Hg/s and a prolongation of IVC from 60 ms (control) to 94 ms. Both changes are consistent with a decreased contractility and performance of LV. A change of tension development in individual ventricular layers underlying this effect is illustrated in To reveal the physiological effects of transmural differences in MSV on development of intraventricular pressure during IVC, we performed further simulation under condition of constant MSV in all ventricular layers. The results illustrated by the dotted line in dp/dt)max as in the case of constant MSV only (from 1780 mm Hg/s (control) to 1100 mm Hg/s). However, the prolongation of IVC duration would be more pronounced (from 60 to 104 ms). Hence the model shows that (dp/dt)max is almost exclusively affected by changes of MSV while the IVC duration is sensitive to changes of both MSV and EMD. These results suggest that while the homogenisation of both MSV and EMD across the LV wall contributes to a decreased contractility of LV, a reduction of transmural gradient of MSV plays a major role in this effect  and Ca2+ transient in human hearts [ICa) during the early transient phase of AP repolarization induced by the presence of larger transient outward potassium current (IKto) [2+ in the sarcoplasmic reticulum (SR) induced by the increased expression of SR Ca2+-ATPase [α myosin heavy chain (MHC) isoform in subepicardial myocytes which exhibit faster cross-bridge cycling kinetics [The heterogeneity in electrophysiological properties of myocytes across the LV wall is commonly known. Substantial transmural distinctions in characteristics of membrane currents and action potential configurations have been demonstrated in myocytes from various species including humans , 35–41. g hearts , 46 and g hearts . Accordig hearts , the disn hearts . As for t (IKto) , 30, 48;+-ATPase , 44, 49;kinetics , 50. Beskinetics  and in dkinetics  might alkinetics , 30. Thikinetics ). Howevekinetics . In addikinetics . Reasonsdp/dt)max  or under higher downregulation of SR Ca2+ pump (SERCA) in subendocardial and midmyocardial cells compared to subepicardial cells as observed in HF [2+ in cardiomyocytes  but also transmurally resynchronise their contraction. A supplementary pharmacological stimulation of subepicardial IKto may be one of the promising ways to achieve this aim.The results of our computational study indicate that a reduction of transmural gradients of EMD and MSV decreases the contractile function of LV because of discoordination of contraction in individual layers of LV. Such intraventricular dyssynchrony would lead to a decline in systolic performance, decreased mechanical efficiency, and a greater metabolic cost of LV contraction. Some changes initiated at cellular level can be identified to contribute to this pathological state. It has been documented that, in heart failure (HF), a greater reduction of rization . Given ttraction , 58, 59  isoform , 61 may  isoform . Besides isoform  may alsoed in HF , 63, 64.The FE model used in this study succumbs to several limitations. Firstly, the model includes only the LV with its geometry approximated by two truncated ellipsoids. The omission of the mechanical interaction between the ventricles, together with the simplification of ventricular shape, affects the motion of the ventricle due to passive and active forces generated within myocardium and thus may slightly influence the calculated results. The kinematics of the ventricle is also affected by the simplified boundary condition at the base which prevents the basal movement of the ventricle. On the other hand, the method of reconstruction of the unloaded geometry is fully applicable to patient-specific geometries recorded under end-diastolic intraventricular pressure. Secondly, the activation pattern used in the model assumes simultaneous depolarization of the whole subendocardial layer and the subsequent spread of excitation towards the epicardium. This is a simplification of the real activation sequence which starts from a few early activated areas in subendocardium and proceeds around the cavity and towards the epicardium . HoweverIKto in synchronisation of contraction across the human LV wall max remained unchanged).The results presented in this study hold true for humans and, to certain extent, for species with similar LV geometry, electromechanical properties of cardiomyocytes, and their similar interconnection with ventricular conduction system (Purkinje fibres). While it is clear that the changes in LV size and shape at the preserved transmural pattern of contraction would lead to substantial changes in the development of intraventricular pressure the impact of the two other factors is not clearly apparent. Nevertheless, considering the potential role of transmural gradient of wall see  it seemsinea pig ) or have, rabbit ). To unh, rabbit . However, rabbit , cow [71, rabbit , and hor, rabbit , as well, rabbit . This imdp/dt)max was reduced. This reduction of contractile power was accompanied by remarkable changes in distribution of LV wall stress. As the contractile properties of living myocytes are governed to a large extent by transmembrane ionic currents, their differential region-dependent pharmacological modulation  might be beneficial in clinical treatment of HF.The presented results suggest that transmural differences in EMD and MSV play an important role in optimization of contractile function of LV. The control model with EMD and MSV distribution prescribed on the basis of experimental results showed the highest contraction efficiency and the increase of intraventricular pressure corresponding to physiological curves. In cases with the values of EMD, MSV, or both kept constant across the LV wall the IVC was prolonged and (


There are clear clinical drivers for right ventricular (RV) T1 mapping in patients with repaired tetralogy of Fallot (rTOF), in whom myocardial fibrosis is implicated in adverse clinical outcomes. However, considerable technical challenges exist, due to thin mobile RV wall with adjacent strong signals from blood and epicardial fat. We prospectively aimed to explore the possible clinical significance of RV diffuse fibrosis in rTOF compared to health.4 We applied Motion-sensitive dephasing (MSPrep) to null blood signal before each shot.1-3 Composite saturation and MSPrep parameters were optimised prior to four 10-cycle scans at saturation-recovery delay Ts≈600 ms and two "anchor" scans at Ts>6 sec,5 run free-breathing twice pre-contrast administration  incorporated 5 shots at the most similar respiratory phase. Imaging parameters: TE = 1.0,2.7,4.3 ms , FA 10°, 6 × 1.9 × 2.1 mm acquired voxels, TGRAPPA rate 4, diastolic shot duration 175 ms. Post-contrast (0.15 mmol/kg Gadovist) RV T1 scans used Ts≈200 ms and "anchor" Ts>3 sec. Separate 11-HB MOLLIs were acquired for blood T1 and LV ECV, at a LV-aligned short-axis plane pre-contrast (5(3)3) and 15 minutes post-contrast (4(1)3(1)2).7We adopted a saturation recovery (SASHA) based approach with MoCo averaging of single-shot fat-water separated images at 1.5T .Data for 22 subjects  were acquired. Two-parameter fit pixelwise T1 maps were generated for each run. Mean RV free wall T1s were measured by two independent observers using CMR42. Inter-observer reproducibility was calculated by coefficient of variation (CoV%) = (within-subject standard deviation/mean) x100%.RV T1 maps were obtained in all subjects, with inter-observer reproducibility of native RV myocardial T1 (CoV 1.8%) and RV ECV (CoV 6.8%). There was no significant difference in RV native T1 and ECV of patients with rTOF compared to the controls who had thin RV wallls Figure . This maRV T1 and ECV quantification is possible with the proposed technique but requires further development. The diagnostic value in this patient population merits further work towards a larger study and to explore histological correlation.


T2 mapping by cardiovascular magnetic resonance (CMR) has been recently proposed as a robust and accurate technique to identify the presence myocardial inflammation. Standardization of post-processing, including assessment of reproducibility and discrimination between health and disease, is necessary for implementation of this technique in clinical practice. Acute myocarditis is characterised by diffuse overspill of intracellular and interstitial edema and inflammatory infiltration. We examined regional T2 values in healthy volunteers (n = 40) and in patients presenting with clinical diagnosis of acute myocarditis (n = 59), and compared several postprocessing approaches to T1 mapping in discrimination between health and disease.All subjects underwent a CMR study for routine assessment of myocardialfunction and scar, as well as T1 and T2 mapping, using 3(3)3(3)5 MOLLI and GraSE sequence, respectively, using 3-Tesla clinical scanner. T2 maps were acquired in apical, midventricular and basal short-axis slice (SAX). Two independent observers measured T2 values from quantitative maps in 16 segments, complete SAX coverage and septal T2 values in patients and controls. Intra- and inter-observer reproducibility of T1 and T2 mapping was assessed using Bland-Altman methods. Discrimination between health and disease was assessed by binary logistic regression.Intra- and inter-observer agreements for native T1  and native T2  ± SD = -0.05 ± 1.85; r = 0.95, p < 0.001 MD ± SD = 0.01 ± 2.5) values across the whole cohort were very high. Similarly, the intra- and inter-observer coefficients of variation (CoV) for T1  and T2  values were low. In healthy controls there were no significant difference between 16 segments (p = 0.21), SASX slices (p = 0.48) nor between segments and midventricular septal sampling (p = 0.67), inidcating no regional variations of T2 values in healthy myocardium.Compared to controls, T2 values were significantly raised in patients with myocarditis . Septal T1 values were not significantly different to SAX T2 values of the same slice . Midventricular septal measurements were similar to segmental T2 values (p = 0.37). Midventricular septal (ConSept) T1 and T2 values were independent discriminators between health controls and patients with myocarditis. Native T1 values were more accurate than T2 values to .We demonstrate that T2 values are useful in detection of myocardial inflammation, whereby septal T2 values are comparable to regional and SAX T2 values in healthy myocardium and acute myocarditis. Both native T1 and T2 using conservative myocardial septal measurements provide accurate, reproducible and easy to apply measurements of mycoardial inflammation.


Diffuse interstitial fibrosis is a common end point in heart failure from multiple etiologies. The post contrast T1 time, extracellular volume (ECV) and partition coefficient (λ) of gadolinium-based contrast media have been used to estimate expansion of myocardial interstitial space, as a surrogate of interstitial fibrosis. The aim of the study was to explore the relationship between T1-based estimates of interstitial expansion and both right (RV) and left (LV) ventricular functional parameters in pulmonary hypertension (PH).We prospectively recruited 8 patients with a diagnosis of PH  who underwent CMR at 3T. CMR studies included functional (bSSFP) cine imaging for assessment of ventricular function. Phase contrast velocity encoded cine imaging was obtained perpendicular to the main pulmonary artery for RV stroke volume assessment. T1 maps (saturation recovery single-shot acquisition (SASHA) were acquired both pre- and 15 minutes after administration of 0.2mmol/kg of Gadobutrol. For each patient, a blood sample was acquired prior to scanning to evaluate hematocrit. Whole-LV as well as septal values of post-contrast T1, ECV and λ were evaluated offline. The relationships between each T1-based estimate and functional parameters were investigated using Spearman's rank correlation (rho).Significant positive correlations were found between septal post contrast T1 time and RV stroke volume indexed (RVSVI)  and between λ and RV end-diastolic volume indexed (RVEDVI)  as well as between whole-LV post contrast T1 times and LV ejection fraction (LVEF) . There were no significant correlations between ECV values and any functional parameters (p>0.05 for each).Trends towards positive correlations between whole-LV post-contrast T1 and LV stroke volume indexed , RVSVI  and RV ejection fraction , and towards negative correlations with RV end systolic volume indexed  were found. There was also a trend towards positive correlation between septal post contrast T1 and LVEF . Furthermore, trends toward negative correlations between septal λ and both RV stroke volume  and RV cardiac output  were revealed.λ increases with dilatation of the RV and shorter post contrast T1 times are seen in patients with increased RV end diastolic volumes and decreased stroke volumes, as well as lower LVEF reflecting a link between diffuse interstitial fibrosis and biventricular functional impairment. Post contrast T1 times and λ may be non-invasive biomarkers of increased interstitial fibrosis seen in maladaptive stages of the disease when progressive dilatation of the RV results in RV systolic dysfunction leading to impairment of LV filling.


INaL). However, its use is limited mostly to patients with coronary artery disease. However, literature has shown its potential benefit in relieving angina in hypertrophic cardiomyopathy. Hereby, we discuss two cases where ranolazine led to improvement in angina refractory to beta-blockers. In conclusion, ranolazine can be considered as a potential antianginal drug in patients with hypertrophic cardiomyopathy refractory to beta-blockers.Ranolazine is an antianginal and works by inhibiting late-sodium current ( Ranolazine is a novel antianginal drug which was approved by FDA a decade ago . At the In 2012, AHA/ACC published its guidelines for treatment of stable angina in patients with coronary artery disease, which included a class IIa recommendation stating ranolazine as a second-line therapeutic agent .INaL) inhibitor. Its role in decreasing diastolic myocardial wall tension and subsequently increasing the coronary blood flow during diastole has been studied [However, over the past decade, our understanding of ranolazine has developed significantly. It has been established that ranolazine acts a late sodium current  showed marked septal hypertrophy with a resting outflow gradient of 80 mmHg. After ruling out other possibilities, diagnosis of chronic stable angina was made. She was discharged after an increase in beta-blocker dosage and was followed up as an outpatient. The patient returned to the ED the next year with similar symptoms. Left heart catheterization showed normal coronaries, and the patient was started on ranolazine, which was titrated up to ranolazine 1000 mg BID as an outpatient. Symptoms improved significantly on combination of metoprolol and ranolazine.A 49-year-old male, with no past medical history, presented to the ED with exertional SOB and episode of lightheadedness. TTE showed severe left ventricular hypertrophy (LVH) with impingement of the septum into left ventricular outflow tract (LVOT) with significant LVOT obstruction and a potential intracavitary gradient >100 mmHg. Left cardiac catheterization showed normal coronaries. Thus, a diagnosis of hypertrophic cardiomyopathy (HCM) was made. He was discharged on metoprolol 25 mg TID. The patient was seen as an outpatient where he complained of anginal symptoms. Provided his heart rate was in low 60 s, he was started on ranolazine 500 mg BID, which was titrated up to 1000 mg BID on the subsequent visit. The patient reported significantly improved symptoms on the combination of metoprolol and ranolazine.Ranolazine is an effective antianginal therapy for patients with hypertrophic cardiomyopathy (HCM). HCM is a very commonly inherited cardiac disorder, with prevalence of 1 in 500 in general population . Chest pINaL in cardiac myocytes isolated from patients with HCM. INaL is a persistent slow influx of sodium ions throughout the action potential of cardiac myocyte. This persistent influx is due to the delayed inactivation of the sodium channel. An increase in intracellular sodium leads to increased intracellular calcium via decreased activity of energy-requiring Na-Ca exchanger (NCX), and in some cases, even via reverse flow through the NCX [Coppini et al.  demonstr the NCX .An increase in intracellular calcium level, in turn, leads to increased tension in the LV myocardial wall which contributes to diastolic dysfunction . This woCoppini et al. also demonstrated lengthening of action potential duration (APD) in cardiac myocytes of HCM patients, also indicatively increased intracytosolic calcium. They successfully reported the in vivo effect of ranolazine in shortening of APD.INaL) inhibitor and prevents the increase in intracytosolic calcium, ultimately increasing the blood supply to the myocardium and relieving anginal symptoms.This consolidates that ranolazine's function as a late sodium current (A study by Gentry et al.  assessedAlthough it requires further assessment by randomized-controlled trials, ranolazine can be considered as a possible antianginal therapy in HCM patients with symptoms refractory to beta-blockers or calcium channel blockers.


The Editorial on the Research TopicVentricular Mechanics in Congenital Heart DiseaseAmerican dancer and choreographer Martha Graham (1894–1991) famously said: “Nothing is more revealing than movement.” Indeed, when thinking about the heart and its incessant dance, a huge amount of information can be derived from analyzing the mechanics of the organ, including mechanical impairments in the presence of disease and particularly in the presence of congenital lesions. This Research Topic aims to present recent research findings on ventricular mechanics in congenital heart disease (CHD) patients, alongside with state-of-the-art reviews that expertly summarize current knowledge in this area.Panesar and Burch). Ghonim et al. review fibrosis and how cardiovascular magnetic resonance (CMR) imaging can aid in its assessment, discussing techniques such as diffusion tensor imaging, tagging, feature tracking, late gadolinium enhancement imaging, and T1 mapping . Finally, Greil et al. look again at the role of medical imaging in this context, but particularly at 3D whole heart CMR imaging, which they indicate as “a cornerstone” in CHD imaging, in the light of its versatile role that includes volumetric analysis in complex geometries, 3D printing, and computational modeling .The reviews cover three crucial components. Panesar and Burch elucidate current knowledge of diastolic dysfunction in CHD, an important yet often overlooked component that can lead to heart failure even in patients with normal systolic function  or the role of isolated tricuspid valve repair in adults with CHD , the insight provided by imaging in looking at both right and left ventricle in patients with CHD is undeniable. Specific imaging modalities also play a crucial role in understanding the mechanics of CHDs, from investigating ventricular function in children with dilated cardiomyopathy using late gadolinium enhancement  to identify an element of systolic dysfunction in young people with cardiomyopathies and aortic stenosis by means of CMR-derived wave intensity analysis . The Research Topic also discusses more methodological considerations with regards to imaging; in particular, Gomez et al. present observations on landmark-based image registration to align CMR and ultrasound images in patients with hypoplastic left heart syndrome and compare ventricular volume measurements obtained with the two modalities .As emerging from this Research Topic, imaging is undeniably a key component when discussing ventricular mechanics, its assessment, and quantification. Original research articles, in fact, demonstrate how different imaging techniques provide us with new insight in CHD patients. Whether assessing patients with tetralogy of Fallot after pulmonary valve replacement . From the point of view of patient-specific modeling, a case study of a 4-month-old patient is presented demonstrating how a multi-domain computational model can recapitulate well the hemodynamics in the Blalock–Taussig shunt and in the pulmonary arteries . Finally, a statistical shape analysis approach is presented as a tool allowing insight into ventricular deformations, presenting models of both patients with repaired aortic stenosis and healthy controls, and putting forward intriguing concepts such as “shape biomarkers” and “motion biomarkers” .This topic also offers a flavor of applications of computational modeling for the purpose of simulating and better understanding ventricular mechanics. Computational modeling is an increasingly powerful tool that can facilitate a patient-specific approach in assessing different aspects of CHD, from hemodynamics to devices to morphology . In thisPopulation-based vs. patient-specific: depending on the pathophysiology of each CHD, and the consequent morphological and functional changes in the heart, these two competing philosophical approaches have emerged as effective methodologies to assess ventricular mechanics in the context of the individual and the population, respectively;The role of imaging and modeling: different imaging modalities, and in particular CMR, clearly emerge as an essential tool for generating new knowledge and insight  into ventricular mechanics in CHD. Similarly, computational modeling has recently reached a stage, where it can be successfully integrated with imaging techniques to enhance diagnosis and outcome prediction.What emerges from these studies is certainly the multifaceted nature of analyzing ventricular motion and ventricular remodeling in patients which CHD. While this conclusion is not surprising in itself, these studies and reviews provide an opportunity to reflect on two key aspects of ventricular mechanics in the light of the latest cutting-edge technological progress as follows:The contributions chosen for this special issue are not just a collection of the latest progress on the key aspects mentioned above. The purpose of this volume is to present new research that can shed light on these crucial points with the aim to link methodological approaches to clinical outcomes and, ultimately, patient benefit. Placing these recent advances into the end-user context is a key last step that will enable a true and purposeful translation of science: all these original research contributions strive to achieve this goal by proposing methods to test new biomarkers of disease progression. Movement, or the absence of, can be extremely revealing, but to what extent novel analyses will allow not only quantification of movement but also possible clinically meaningful predictions in the light of movement abnormalities? The simultaneous development of advanced imaging techniques, methodologies for image processing, and computational modeling, as well as the relentless progress made by the research community world-wide to integrate these tools both among each other and within clinical practice, can hold the key to this fundamental question. Ultimately, CHDs encompass a wide range of anatomical and functional maladaptive traits, and as such there is no single recipe for positive outcomes in the clinic. Rather, the ability to understand and interpret the pathological changes from a mechanistic perspective is pivotal to select the most effective approach in the context of each disease.Future directions include continued efforts for large-scale validation of computational models, as well as the development of user-friendly platforms to render the application of patient-specific simulations not only feasible but also accessible and efficient in the clinical domain. The progress in imaging acquisition techniques and processing presented in this Research Topic also holds significant potential for developing disease classifiers from image feature quantification in conjunction with machine learning algorithms. Another exciting area of future development outside the field of imaging and modeling would in fact be to explore the possibility of developing risk scoring methodologies, such as algorithms trained using electronic health records . The latWhile some of the studies presented in this Research Topic are based on too small sample sizes to lead directly to clinical applications, the subtlety of the processes analyzed, together with the knowledge that some of the validated indices routinely used in adults are not necessarily informative in children , should GB and AdV have contributed equally to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The diagnosis of peri-procedural myocardial infarction is complex, especially after the emergence of high-sensitivity markers of myocardial necrosis.In this study, patients with normal baseline cardiac biomarkers and formal indication for elective on-pump coronary bypass surgery were evaluated. Electrocardiograms, cardiac biomarkers, and cardiac magnetic resonance imaging with late gadolinium enhancement were performed before and after procedures. Myocardial infarction was defined as more than ten times the upper reference limit of the 99th percentile for troponin I and for creatine kinase isoform (CK-MB) and by the findings of new late gadolinium enhancement on cardiac magnetic resonance. We assessed the release of cardiac biomarkers in patients with no evidence of myocardial infarction on cardiac magnetic resonance.Of 75 patients referred for on-pump coronary bypass surgery, 54 (100%) did not have evidence of myocardial infarction on cardiac magnetic resonance. However, all had a peak troponin I above the 99th percentile; 52 (96%) had an elevation 10 times higher than the 99th percentile. Regarding CK-MB, 54 (100%) patients had a peak CK-MB above the 99th percentile limit, and only 13 (24%) had an elevation greater than 10 times the 99th percentile. The median value of troponin I peak was 3.15 (1.2 to 3.9) ng/mL, which represented 78.7 times the 99th percentile.In this study, different from CK-MB findings, troponin was significantly increased in the absence of myocardial infarction on cardiac magnetic resonance. Thus, CK-MB was more accurate than troponin I for excluding procedure-related myocardial infarction. These data suggest a higher troponin cutoff for the diagnosis of coronary bypass surgery related myocardial infarction.http://www.isrctn.com/ISRCTN09454308. Registered 08 May 2012. Myocardial necrosis biomarkers are frequently elevated after cardiac revascularization procedures. However, the diagnosis of acute myocardial infarction (MI) after a revascularization procedure is still a controversial issue. This inability to diagnose MI makes it more difficult to establish a specific therapeutic strategy. With the appearance of high-sensitivity troponins, a myriad of false-positive diagnoses for myocardial infarction have emerged. In 2000 and 2007 in an attempt to standardize the criteria for diagnosing MI, the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the World Heart Federation formed a joint task force to address this issue, but the task force was unable to make a satisfactory decision. Therefore, the problem still remained. To reduce diagnostic mistakes, in 2012, this same group arbitrarily raised the cutoff point to 10 times the 99th percentile, but with no solid scientific basis for doing so . CardiacParallel to the increased sensitivity of troponin assays, imaging methods have achieved better accuracy for exclusion of the diagnosis of myocardial infarction. Thus, due to the limitations on the interpretation of biomarkers after coronary artery bypass grafting (CABG) and the difficulty of excluding MI, cardiac magnetic resonance imaging (CMR) has enabled a more detailed evaluation of the myocardium.Therefore, in this study, we aimed to examine the release of biomarkers after CABG in patients with no evidence of late enhancement on CMR.Details of the study design, protocol, patient selection, and inclusion criteria have been previously reported . BrieflyThe primary outcome was the occurrence of MI based on the release of the biomarkers, cTnI and CK-MB, in patients with no late gadolinium enhancement (LGE) assessed by CMR.In accordance with current best practices, the same team of surgeons with experience in ONCAB performed the procedures. Surgical access to the heart was through a standard median sternotomy in all cases. All incisions and closure techniques were performed in the same way in all patients to limit variability among patients.CMR was performed before and after the surgical procedure. CMR, considered the gold standard, allows high-precision assessment that is reproducible in the same test. Recent studies indicate that CMR detects MI very accurately and provides results similar or superior to results with radionuclide imaging –10.o) following a 5-min time delay after the administration of 0.1 mmol/kg contrast agent . Images were acquired in 2 long-axis planes and in a short-axis stack covering the entire left ventricle. The inversion time was meticulously adjusted throughout the acquisition to obtain optimal nulling of remote normal myocardium. The slice thickness at the apex was reduced to 5 mm to avoid a partial volume effect. MI was defined as the identification of hyper-enhancement in the myocardium on CMR. Infarcted regions exhibit this phenomenon, which might be due to an increased volume of distribution of the contrast agent, because of rupture of myocyte membranes and slow contrast washout [All patients underwent CMR 2 days before the intervention and 6 days after each invasive procedure during the hospitalization period. A 1.5-T Achieva Magnetic Resonance scanner  was used. Steady-state free precession cine images were acquired in 2 long-axis (2 and 4 chambers) views and 8 to 10 short-axis views of the left ventricle. Contrast-enhanced images were acquired in long- and short-axis planes identical to the cine images. Typical voxel size was 1.6 × 2.1 × 8 mm, with a reconstruction matrix of 528 and a reconstructed voxel size of 0.6 mm. The method for acquiring and analyzing CMR was standardized in our service and was reproduced according to conventional techniques , 12. DelAll areas of late gadolinium-diethylene-triamine-pentaacetic acid (DTPA) hyper-enhancement were quantified by 2 experienced observers who interpreted the LGE while blinded to the interventional technique and biochemical data. When measurements differed, a third observer performed a review, and a consensus was obtained. Hyper-enhanced pixels were defined as those with image intensities exceeding 2 standard deviations greater than the mean of image intensities in a remote myocardial region in the same image. Pre-intervention and post-intervention scans were read side by side in both surgical techniques, with and without extracorporeal circulation.All blood samples for measurement of cTnI and CK-MB were collected immediately before and 6, 12, 24, 36, 48, and 72 h after on-pump CABG. The surgeon and clinical team were blinded to the CK-MB or cTnI data. All samples were centrifuged at 3000 rpm for 20 min and analyzed within 2 h after collection. Analyses of cTnI and CK-MB were performed using an ADVIA Centaur immunoassay analyzer . According to the manufacturer, the lower limit of detection of cTnI using the high-sensitivity Ultra kit is 0.006 ng/mL, and the 99th percentile upper reference limit (URL) is 0.04 ng/mL. The assay precision represented by the percentage coefficient of variation is 10% at 0.03 ng/mL. The detection limit of the CK-MB mass kit (Acute Care™ CK-MB assay Siemens™) is 0.18 ng/mL. Cutoff values at the 99th percentile are 3.8 ng/mL for women and 4.4 ng/mL for men. The coefficients of variations for CK-MB mass, as specified by the manufacturer, are 3.91% at 3.55 ng/mL and 3.67% at 80.16 ng/mL.According to the Third Universal Definition , MI typeTwelve-lead electrocardiograms (EKG) were obtained from each patient immediately before and 6, 12, 24, and 36 h after CABG. For the identification of new Q waves, we used the Minnesota code, which is used extensively in epidemiology studies and large-scale clinical trials .All patients provided written informed consent and were assigned to a treatment group. The Ethics Committee of the Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil, approved the trial. All procedures were performed in accordance with the Declaration of Helsinki.t test and the unpaired-sample t test were used to compare means within the study group or between subgroups. The chi-square and the Fisher exact tests were used for comparison of discrete variables. Continuous variables without normal distribution were compared using the Mann-Whitney U test, and correlation between such variables was made with the Spearman rank test. Values of p < 0.05 were considered statistically significant.Values are expressed as mean and standard deviation or median and interquartile range, as appropriate. The paired-sample Between March 2012 and April 2014, 326 consecutive patients who met the inclusion criteria were screened. Of these patients, 107 (32.8%) were excluded  ng/mL, which corresponds to 78.7 times the 99th percentile. Two (4%) patients had elevation just above the 99th percentile, and 52 (96%) remaining patients had elevation above 10 times the 99th percentile. There were no patients with a cTnI value below the 99th percentile after the surgical procedure Fig. .Fig. 2PeRegarding CK-MB peak, the median value was 23.0 ng/mL (14.2 to 38.3 ng/mL). Additionally, 41 (76%) patients had elevation above the 99th percentile, and 13 (24%) had an increase higher than 10 times the 99th percentile Fig. .The pattern of cTnI elevation in each moment of evaluation after surgery is shown in the chart below Fig. . Values p < 0.001 in all groups.The comparisons of the levels of cTnI in the different periods after the procedure showed a statistically significant difference, The pattern of CK-MB elevation in each moment after surgery is shown in the chart below, respectively Fig. . Only a p < 0.001 in both groups.The comparisons of CK-MB values in the different periods after the procedure showed statistically significant differences, All of the 54 patients who were free of late enhancement on the CMR after the procedure and who were selected for this study underwent ECG at entry and sequentially. None of them had a new bundle-branch block, ischemic ST-segment, new pathologic Q wave conduction disorders, or a new Q wave after the procedure.All patients had preserved glomerular filtration rate on admission. Sequential measures of renal function indicated that no loss of this function occurred.In this prospective trial based on current guidelines, we found distinct results when cTnI and CK-MB were simultaneously analyzed in patients after surgical myocardial procedures. All patients had elevated cTnI above the 99th percentile after surgery, with the majority having more than 10 times, reaching an average of 70 times this threshold. Conversely, we found the release of CK-MB predominantly below the recommended threshold of 10 times the 99th percentile. Therefore, our findings conflict with the recommendations of the 2012 European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Foundation Joint Task Force for the diagnosis of myocardial infarction after surgical revascularization.In this scenario, the EKG remained similar before and after interventions independently of the release of biomarkers. In addition, CMR likewise remained unchanged, without a new delayed enhancement after the procedure.Over the last decade, elective CABG has progressed to a very standardized and safe surgical procedure with low mortality and low rates of myocardial events . Thus, tA study aimed at identifying the release of biomarkers following myocardial revascularization conducted by Pegg et al.  identifiThe evident release of cTnI in the absence of myocardial necrosis is still questioned in the literature. As a confounding factor, advances in cTnI accuracy after high-sensitivity cTnI onset have been recently observed . It can With the emergence of high-sensitivity troponins, the relationship between the increase in the sensitivity thereof and the increasing rise in false diagnoses has already been described . CurrentAssuming that cardiac biomarkers have limited diagnostic accuracy in myocardial necrosis, the challenges faced for the establishment of definitive values for the diagnosis of myocardial damage include new cutoff values for cTnI. Furthermore, the diagnosis of this condition cannot be exclusively based on cardiac biomarkers or EKG. It is reasonable to include CMR in the set of tools for the accurate diagnosis of procedure-related myocardial injury.In this study, different from CK-MB findings, troponin was significantly increased in the absence of myocardial infarction on cardiac resonance imaging. Thus, CK-MB was more accurate than cTnI for excluding procedure-related MI. These data suggest a higher troponin cutoff for the diagnosis of CABG-related MI.


Three major mechanisms contribute to right ventricular (RV) pump function: (i) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (ii) inward movement of the RV free wall; (iii) bulging of the interventricular septum into the RV and stretching the free wall over the septum. The relative contribution of the aforementioned mechanisms to RV pump function may change in different pathological conditions.Our aim was to develop a custom method to separately assess the extent of longitudinal, radial and anteroposterior displacement of the RV walls and to quantify their relative contribution to global RV ejection fraction using 3D data sets obtained by echocardiography.Accordingly, we decomposed the movement of the exported RV beutel wall in a vertex based manner. The volumes of the beutels accounting for the RV wall motion in only one direction  were calculated at each time frame using the signed tetrahedron method. Then, the relative contribution of the RV wall motion along the three different directions to global RV ejection fraction was calculated either as the ratio of the given direction’s ejection fraction to global ejection fraction and as the frame-by-frame RV volume change (∆V/∆t) along the three motion directions.The ReVISION  method may contribute to a better understanding of the pathophysiology of RV mechanical adaptations to different loading conditions and diseases.The online version of this article (doi:10.1186/s12947-017-0100-0) contains supplementary material, which is available to authorized users. During the last decades the right side of the heart has gained more and more attention. Compared to the relatively simple conical shape of the left ventricle, the right ventricle (RV) shows a more complex anatomical structure. When viewed from anterior-lateral view it shows a triangular shape, whereas when it is viewed from a short axis cross-section it has a crescent shape, partially wrapping the left ventricle. Anatomically, the RV is traditionally divided into three parts: the inlet portion, which consists of the tricuspid valve, chordae tendinae and the papillary muscles, the apical part with trabeculated muscle, and the outlet portion, also called the infundibulum with the pulmonary valve, which seperates the ventricle from the pulmonary trunk . In contThree main mechanisms contribute to RV pump function: (i) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (ii) inward movement of the RV free wall; (iii) bulging of the interventricular septum into the RV during the left ventricular contraction and stretching the free wall of the RV over the septum . Since tThe complexity of RV geometry and mechanics may in part explain current difficulties in the assessment of its function using conventional tomographic techniques. The most widely used two-dimensional transthoracic echocardiography provides several parameters, however, the majority of the conventional measures refer only to the longitudinal contraction of the chamber . Three-dAccordingly, our aim was to develop a custom method to separately quantify the extent of longitudinal, radial and anteroposterior displacement of the RV walls and their relative contribution to the global RV ejection fraction using 3D data sets of the RV obtained by echocardiography.Current matrix-array transducers permit the acquisition of 3D volumetric data of the RV during routine transthoracic echocardiographic examinations . Dedicat1,…, mn series of meshes where We developed the ReVISION  method using the Unity3D engine to decompose the motion of the exported RV beutel along three orthogonal axes and calculate the respective volume at each time frame. Note that the Euclidean axes in the dedicated software’s output correspond to the anatomically relevant ones . We decomposed the movement of the RV wall in a vertex-based manner  Figs. , 3 and 4Additional file 1: Right ventricular model with all motion directions enabled . (MP4 468 kb)Additional file 2: Right ventricular model with only longitudinal motion enabled . (MP4 486 kb)Additional file 3: Right ventricular model with only radial motion enabled . (MP4 426 kb)Additional file 4: Right ventricular model with only anteroposterior motion enabled (Animation 4 – anteroposterior only.mp4). (MP4 728 kb)The volumes of the beutels accounting for the RV wall motion in only one direction  were calculated at each time frame using the signed tetrahedron method  Fig. 3)3). No trP be the set triangles of an miy mesh. For each p ∈ P let p = {, …, } The volume of tetrahedron bounded by the vertices of p and the origin:Let Vp is signed, meaning that the values may be negative in case the normal vector of the polygon points towards the origin . The volume of the mesh is the sum of the signed Vp volumes:Note that Ejection fraction is the most common measure of RV pump function and it is defined as the difference between end-diastolic and end-systolic volumes indexed to end-diastolic volume. Using the ReVISION method, volume changes due to the RV wall motion along the three directions can be separately quantified and the corresponding ejection fraction value can be calculated . The relative contribution of the RV wall motion along the three different directions to global RV ejection fraction can be expressed by the ratio of the given direction’s ejection fraction to global ejection fraction. It may be also clinically relevant to evaluate the frame-by-frame RV volume change along the three motion directions. By calculating the difference quotients between the given frames (∆V/∆t), we were able to estimate the relative contribution of longitudinal, radial and anteroposterior motion to systolic, and also to diastolic RV function Fig. . It is iWe have shown that, using surface rendered data sets of the RV obtained with transthoracic 3D echocardiography, it is possible to decompose the displacement of the RV wall in a vertex-based manner. The volumes of the beutels accounting for the RV wall motion in only one direction  can be calculated at each time frame using the signed tetrahedron method. Using the ReVISION, we can compute novel parameters of RV function  along the three aforementioned directions). These parameters may help to improve our understanding of the pathophysiology of RV mechanical adaptations to different loading conditions and diseases Table .Table 1PThe RV is a significant contributor to global heart function and therefore, a better understanding of its functional pattern may be of high clinical interest. Despite the fact that the relative contribution of the longitudinal shortening, radial displacement and septal thickening to global RV function may change in different diseases affecting the RV , there iEchocardiography is a widely used, non-invasive imaging modality to describe cardiac morphology and function. However, ultrasonic assessment of the RV is challenging due to the complex anatomy of the chamber. Conventional two-dimensional acquisition protocols require to obtain several imaging views using the parasternal, apical and subcostal approaches. The most commonly used echocardiographic measures to characterize RV morphology are simple linear diameters, while functional aspects are mainly investigated by measuring the tricuspid annular plane systolic excursion (TAPSE) and the RV fractional area change (FAC) . The latUsing 3D echocardiographic datasets, RV volumes and global ejection fraction can be measured with a good correlation with MRI results , 9. HoweThe underlying causes of the varying relative contribution of these mechanisms to global RV function in different cardiac conditions remain to be clarified. Beyond the mechanical effects of volume and/or pressure overload, there are several other and often overlapping factors that may be responsible for these findings. Several research groups hypothesized that the myocardial fiber architecture of the RV can change in certain conditions. Classical anatomical dissections revealed that in patients with congenital heart malformations such as Tetralogy of Fallot, pulmonary or tricuspid atresia, significant changes can be observed in the myocardial fiber arrangement within the RV wall. These changes include the more oblique orientation of the longitudinal layer, and also the presence of a middle circumferential layer which is absent from physiological conditions , 26. PreCurrent literature is scarce about the clinical value of RV peak ejection rate and peak filling rate due to their previously complicated measurements with radionuclide ventriculography , 37. 3D Since the possibility to quantify the relative contribution of the different components of right ventricular wall motion to global right ventricular ejection fraction would be of high clinical interest in both physiological and pathological cardiac conditions, we developed the ReVISION method to obtain these components separately from 3D data sets of the right ventricle by echocardiography. Since there is no reference method to test the accuracy of our measurements, only prospective outcome studies can assess the clinical value of our approach.www.revisionmethod.comThe ReVISION software can be freely downloaded for scientific purposes from


P = 0.026) and RV-LGE  were independent predictors of mortality in CA. For all amyloid patients, log NT-proBNP  and RV-LGE  were identified as independent predictors. RVESVi and RV-LGE are independent predictors of survival and evaluation of RV by CMR enables risk stratification in patients with CA.Few studies have focused on right ventricular (RV) involvement in cardiac amyloidosis (CA). We investigated the prognostic value of RV assessment by cardiovascular magnetic resonance (CMR) in CA. In 2011–2014, consecutive patients with suspected CA referred for CMR were retrospectively evaluated. Demographic and baseline clinical characteristics were collected. Healthy volunteers were matched for sex and age and served as controls. All subjects underwent a contrast-enhanced CMR examination. RV size, function, and late gadolinium enhancement (LGE) were analyzed. All deaths during follow-up were recorded. Sixty-one patients  were included; CA was diagnosed in 47 (77.0%) patients. CA patients displayed decreased biventricular ejection fraction, elevated left ventricular mass index, and increased biventricular end-systolic volume index (ESVi) compared with controls. A total of 27 deaths (57.4%) occurred in the CA group at 21-month median follow-up. Multivariable analysis demonstrated that RVESVi (HR 1.033, 95% CI 1.004–1.063,  Amyloidosis is a group of rare diseases characterized by extracellular deposition of insoluble abnormal fibrillar proteins derived from various precursor proteins that leads to multi-organ structural alterations and functional impairment . CardiacMost studies have emphasized the importance of left ventricular (LV) diastolic dysfunction in CA, but the value of the right ventricular (RV) function is usually ignored –6. In thCardiovascular magnetic resonance (CMR) imaging is the reference modality for the quantification of RV volumes and systolic function . Furthern = 21), kidney (n = 19), bone marrow (n = 14), lymph node (n = 3), bronchus (n = 2), rectum (n = 2), liver (n = 2), and skin (n = 2). Lack of cardiac involvement was defined as normal LV wall thickness without LGE on CMR and normal serum biomarkers. Three patients were excluded due to receiving chemotherapy before CMR, and one patient was excluded from the analysis due to incomplete data on baseline characteristics, resulting in a study population of 61 patients. Figure Between 2011 and 2014, 65 consecutive patients with biopsy-proven AL amyloidosis in any organ system underwent CMR at West China Hospital, Sichuan University. In all cases, histological proof of systemic AL amyloidosis was obtained, with pink homogeneous material on hematoxylin and eosin staining, apple-green birefringence staining with Congo red, or amyloid fibers on electron microscopy. AL amyloidosis was further confirmed by immunohistochemical staining and demonstrating the presence of clonal plasma dyscrasias. Positive biopsy sites included abdominal fat  and normal 12-lead electrocardiography (ECG) and showed no history or symptoms of cardiovascular disease or diabetes. All subjects included in the study provided written informed consent, and the study was approved by the Institutional Review Board of West China Hospital, Sichuan University.ECG-gated CMR was performed during a breath-hold using a 3.0 T scanner  with an eight-channel phased array body coil. Steady-state free precession cine images were acquired in consecutive short-axis slices covering the whole ventricle and three long-axis slices . The parameters of the SSFP cine were as follows: repetition time (TR) 3.4 ms, echo time (TE) 1.3 ms, flip angle 50°, field of view (FOV) 340 mm, matrix size 256 × 144, slice thickness 8 mm, no gap. LGE images were acquired at 3–5 and 10–15 min, respectively, after intravenous administration of 0.15 mmol/kg gadopentetate dimeglumine  using an inversion recovery turbo-flash sequence in identical views .3). The volumes of individual slices were summated to obtain the LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV), which were then used to calculate LVEF [LVEF = 100 × (LVEDV − LVESV)/LVEDV] and LV mass . LVEDV index (LVEDVi) and LVESV index (LVESVi) were defined as the ratio of LVEDV and LVESV, respectively, to body surface area. The papillary muscles were included in the LV volumes and excluded in the mass calculations.Images were analyzed on a workstation using Q-MASS 7.6 software . Briefly, endocardial and epicardial borders were traced manually by an experienced observer in the end-diastolic and end-systolic frames on successive short-axis cine images. Ventricular volume was calculated by volume summation of consecutive short-axis slices. LVEF was calculated as: (volume end diastole − volume end systole)/volume end diastole). LV mass was derived by the summation of the disk method and by multiplying muscle volume by its density  were not traced. From the identified borders, RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV) were calculated and indexed to body surface area.LGE images were first assessed visually for the presence and location of LGE by two experienced readers (D.Y. and H.L.) that were blinded to patient profiles and clinical outcome, with any disagreement adjudicated by a third expert reader (YCC). To exclude artifact, LGE was deemed present only if visible in two orthogonal views. Because the classification of cause of death is often problematic in AL amyloidosis, all-cause mortality due to progressive disease was the primary endpoint. Follow-up data were obtained by review of the patient’s hospital chart or telephone interview with the patient or relative. There was 100% follow-up.t test or analysis of variance. Differences among the three groups were assessed by one-way ANOVA or the Kruskal–Wallis test, followed by post hoc pairwise comparisons using Bonferroni correction. Nonparametrically distributed continuous data were presented as medians with interquartile range (IQR) and compared by the Wilcoxon rank sum test or Kruskal–Wallis test. NT-proBNP and troponin T were log (ln) transformed to achieve normality for further analysis. Variables for which P values in the univariate analysis were smaller than 0.05 were entered in a multivariate Cox proportional hazard model. Factors independently associated with the primary endpoint were identified using backward stepwise selection. We tested four models. The first model included the significant clinical variables, the second model included all significant biological variables, the third model included the significant functional and tissue characteristics of the CMR, and the last model included all significant clinical, biological, and CMR variables. Area under the curve (AUC) of the receiver operating characteristic (ROC) analysis was performed to determine the prognostic value and optimal cut-off point. Sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) using relevant cut-offs were computed. Survival curves were plotted with the Kaplan–Meier method using the log rank test for comparisons. All statistical analyses were performed using SPSS 17.0 software for Windows . P < 0.05 was considered statistically significant.Data were expressed as the mean + standard deviation (SD). Continuous variables were summarized as the mean ± SD where normally distributed with equal variances and compared by Student’s Sixty-one patients with AL amyloidosis  were included in the study; CA was diagnosed in 47 (77.0%) patients. The CA patients’ mean age was 60 years (IQR 54–68), 28 (59.6%) were men, and six (12.7%) had atrial fibrillation. The baseline demographic and clinical characteristics of the patients and healthy volunteers are summarized in Table 2. LV-LGE and RV-LGE were less frequently observed in the survivor group.Survivors and non-survivors at 6 months follow-up did not differ in age, sex, low voltage, or chemotherapy Table . FourteeP = 0.026 combined model) and RV-LGE  remained significantly associated with the primary outcome when all significant variables of clinical, laboratory, and CMR model were added to the model. ROC analysis revealed that the AUC of RVESVi was 0.757 . The overall survival of the RV-LGE-negative group was superior to that of the RV-LGE-positive group  in the CA group. Six deaths occurred within 1 month of AL amyloidosis diagnosis, 17 within 6 months, and 24 within 1 year. No deaths occurred in patients without CA. The results of the univariate analyses in CA patients are presented in Table % in the P = 0.004 and HR 4.149, 95% CI 1.623–10.607, P = 0.003, respectively) after adjustment for the significant variables of the clinical, biological, and CMR model  are reported in Table Cardiac involvement is common in patients with AL amyloidosis and is characterized by a poor prognosis with limited treatment options . In the LGE CMR is a robust technique used to assess myocardial irreversible injury, such as myocardial focal fibrosis  and amylAs LV ejection fraction is generally preserved in patients with CA, other markers of myocardial dysfunction are needed for prognosis. Previous echocardiographic studies have shown that changes in RV function have independent prognostic power in patients with amyloidosis, such as Tei index ≥0.9 , TAPSE <E/A and E/E′ ratios [Previous echocardiographic studies have demonstrated that changes in LV function play a role in predicting mortality, such as mitral inflow deceleration time  and E/A ′ ratios . An echo′ ratios . We foun′ ratios .2 identified a cohort of patients who may be at high risk of death. There is some variability in survival and clinical course in AL patients, and it is important to be able to stratify these patients to guide therapeutic decisions. Prospective trials aimed at early detection of poor prognosis and employment of aggressive treatment strategies such as transplantation or chemotherapy with stem cell transplantation should be conducted to provide therapeutic guidance.We investigated the prognostic value of RV volume, function, and tissue characteristics using CMR in AL patients with CA. On multivariate analysis, RVESVi and RV-LGE are independently associated with an adverse outcome. Furthermore, in patients with CA, an RVESVi greater than 32 mL/mThe present study has several limitations. The patient sample size was relatively small; however, given the low prevalence of CA, our study numbers compare favorably with previously published studies. Endomyocardial biopsy was not performed, but AL amyloidosis was found in other organs, and all patients met the criteria for clinical diagnosis of CA. Diagnostic algorithms integrating clinical presentation, electrocardiography, echocardiography, and blood biomarkers can obviate the need for myocardial biopsy. Furthermore, cardiac response assessment is not regularly performed after chemotherapy at our center. Finally, our study was performed in a tertiary referral center, and our results may not be extrapolated to all AL populations.RV size and tissue characteristics are significantly abnormal in patients with cardiac amyloid, in which the accurate assessment of RV by CMR provides significant independent predicting value for mortality in patients with amyloidosis.