At present, multi-detector cardiac CT has been widely applied in the detection of heart valve morphology and function. This study aims to compare the coronary CT angiography and trans-thoracic echocardiography for patients with mitral valve prolapse.CT angiography and trans-thoracic echocardiography were adopted to detect the movement range and thickness of valvula bicuspidalis. The ultrasonic parameters of CT angiography were considered as standard reference value.P < 0.001). Based on the intercept point on the ROC curve, the sensitivity and accuracy of mitral valve amplitude detected by CT angiography was 69.2 and 95.6%, the false positive and false negative rate was 5.2 and 32.4%, the predicted value of positive and negative was 92.9 and 76.9% and the consistency rate of motion range and leaf thickness detected by CT angiography was 83.3 and 47.5%. Trans-thoracic echocardiography showed that the thickness and motion range of mitral leaflet was (1.95 ± 0.22) mm and (1.5 ± 2.28) mm. The thickness and motion range of mitral leaflet that detected by CT was (2.00 ± 0.54) mm and (3.76 ± 2.1) mm.Receiver operating characteristic (ROC) curve showed that the area of mitral valve motion amplitude under ROC curve was 95% detected by CT angiography with statistical significance (The accuracy and reliability of CT angiography for patients with mitral valve prolapse are higher than those of trans-thoracic echocardiography. Mitral valve prolapse is one of the most common heart valve diseases. Epidemiologic studies have demonstrated that the morbidity rate of mitral valve prolapse is approximately 3–6%. A majority of patients have no obvious clinical manifestations. If severe mitral regurgitation occurs in the late period, the patients have to undergo mitral valve repair. Therefore, the monitoring and accurate diagnosis of high-risk patients is of great significance –4. If paFrom August 1st, 2014 to July 31st, 2015, patients with mitral valve prolapse by physical examination and trans-thoracic echocardiography were recruited. Then, valve repair surgery was carried out and re-examined by CT scan at 3 months after initial diagnosis. Exclusion criteria: patients with renal insufficiency (serum creatinine> 1.5 mg/dl), thyroid diseases, iodine allergy, progressive heart failure, atrial fibrillation and other types of arhythmia, pregnant women, those with previous history of myocardial infarction, heart ischemia or other diseases occurring in recent 3 months and those unwilling to participate in this study were excluded. The diagnosis of mitral valve prolapse was confirmed by two experienced physicians, who reviewed the results of trans-thoracic echocardiography. If the heart rate was > 70 times/min before the examination, β-receptor blocking pharmacon (25–50 mg metoprolol) was injected to control the heart rate at 65 times/min. A total of 90 eiligible patients completed the study. Written informed consents were obtained from all patients or family members.Conventional trans-thoracic echocardiography was performed by experienced physician . Mitral valve prolapse was defined as valve cusp displacement > 2 mm or the parasternal direction of the long axis tended to the left atrial direction. Mitral valve leaflet thickness was measured under two- to four-chamber view similar to CT scan. The severe degree of mitral regurgitation, end-diastole and end-systole of left ventricular volume, ejection fraction, peak pulmonary arterial pressure and other parameters were also measured.Patients were processed by 64-row CT inspection after 3 months of trans-thoracic echocardiography . The related parameters were set as followed: level alignment was 2 × 32 × 0.6 mm; profile acquisition was 64 × 0.6 mm; pitch of screw thread was 0.2; slew time was 350 ms; tube voltage was 120 kV; tube current time was 600 mAs. A 70-100 ml nonionic iodine contrast agent was applied in the detection, washed by 40 ml physiological saline and administered via intravenous dripping at a rate of 3 ml/ seconds along the elbow vein. The bolus technique was utilized to calculate the scanning delay.Besides the function of coronary artery with CT examination, the thickness and motion range of mitral valve leaflet were collected, which was 25–30% data during R-R period, because the motion range of valve cusp in this section reached the maximal value. The data was processed by the late stage of multi-planar reconstruction, we defined three-chamber plane generated in the direction of parasternal longitudinal axis wasdefined as passing through the left ventricular long axis and left ventricular outflow tract, equivalent to the left coronal oblique angle. Two-chamber plane was defined as the left ventricular geometric center vertical long axis direction, equivalent to the sagittal oblique view passing through the ventriculus sinister, left atrium and center of mitral valve. Four-chamber plane was generated by the recombining of left ventricular short axis, which was located in the middle of the left ventricle. It was defined as a transitional plane passing through the left ventricular center, diaphragm and right ventricular free wall. During the systole period (25–30% R-R period), the maximum vertical distance was recorded between the mitral valve leaflet and annulus plane under three-chamber view, equivalent to the long axis view of trans-thoracic echocardiography. Left ventricular offset was defined as negative value, and its left atrial offset was defined as positive value. The thickness of valve cusp was measured under two- to four-chamber view, excluding the calcified part. The explanation of checking image was finished by two experienced clinicians, who were blind to the results of trans-thoracic echocardiography.P value of less than 0.05 was considered as statistical significance.SPSS 20.0 statistical software was utilized for data analysis. The data were expressed as mean ± standard deviation (SD). Continuous variables were statistically compared by t-test. Classified variables were compared by chi-square test or Fisher exact test. The correlation analysis was processed by Pearson’s correlation analysis examination. The ROC curve was adopted to detect the cut-off point. The sensitivity, specificity, false positive, false negative and other parameters were detected and measured. A A total of 90 patients were included in the study, aged 61.2 ± 13.4) years old on average, the male/female ratio was 3:2, (56.3 ± 11.9) years old for the male and (66.4 ± 12.7) years old for the female. The average systolic pressure, diastolic pressure and heart rate before trans-thoracic echocardiography and CT detection were (131 ± 12) mmHg vs. (128 ± 14) mmHg, (70 ± 8) mmHg vs. (72 ± 8) mmHg, (69 ± 10) times/min vs. (68 ± 9) times/min, respectively, as illustrated in Table .2 ± 13.4Trans-thoracic echocardiography showed that the thickness and motion range of mitral leaflet were (1.95 ± 0.22) mm and (1.5 ± 2.28) mm. The cardiac examination results were regarded as the reference standard. The thickness and motion range of mitral leaflet that detected by CT were (2 ± 0.54) mm and (3.76 ± 2.1) mm.p = 0.36). The optimal cut-off point of using CT to detect leaf thickness was 1.6 mm. The sensitivity of mitral valve prolapse was 94.2%, the specificity was 95.1%, the false positive was 5.1%, the false negative was 94.9%, the positive predictive value (PPV) was 48% and the negative predictive value (NPV) was 52%. The consistency between CT angiography and trans-thoracic echocardiography was 47.5%.ROC analysis of the data obtained by CT angiography showed that compared with the results of trans-thoracic echocardiography, the area under standard curve of valve leaf thickness detected by CT was 57% (95%CI: 0.42–0.76) with no statistical significance (P < 0.05). The motion range of valve cusp was a vital index of diagnosing mitral valve prolapse. The cut-off point in ROC curve was 2.5 mm, the sensitivity of mitral valve prolapse was 69.2%, specificity was 95.6%, the false positive was 5.2%, the false negative was 32.4%, the positive predictive value (PPV) was 93.1% and the negative predictive value (NPV) was 77.8%. The consistency between CT angiography and trans-thoracic echocardiography was 83.3%.  with statistical significance (P < 0.05).According to the obtained data, 70% direct correlation existed between CT angiography and trans-thoracic echocardiography in the measurement of leaf thickness with statistical significance. The relativity of valve cusp motion range was 95%, which also had statistical significance , but when applied CT angiography for detecting mitral valve leaflet movement (> 2.5 mm in this study), the diagnosis of mitral valve prolapse was established. The PPV in previous study was 87, 80 and 93%. The NPV in this study was 77.8%, which was basically the same with the result of 80, 83 and 91% in previous study. In the detection of mitral valve thickness, the relativity of these two methods was 70%, which indicated that the reliability of diagnosing mitral valve thickness was pretty well. The overall accuracy of mitral valve prolapse detected by CT angiography was 83.3%, so it was a reliable detection method.CT also has the advantage of less radiation exposure, side effects of contrast agent and lower cost, etc –24 The rThis is a retrospective investigation. Therefore, the preliminary findings obtained in current article remain to be further validated in a prospective study. In addition, the detection methods can be widened and the sample size can be enlarged to confirm the obtained conclusion.


MitraClip is the sole percutaneous device approved for functional mitral regurgitation  but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD).Err) in the sub-valvular myocardium were calculated.Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV_VOLUME) and MitraClip was simulated with contracting beam elements  placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedure-related radial strain ). Furthermore, MitraClip in ↑LV_VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p = 0.0268) and in PL by 22.5±23.7 kPa (p = 0.0101).MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement. Functional mitral regurgitation (FMR) in patients with coronary artery disease (FMR-CAD) occurs in 1.2 to 2.1 million patients in the United States and of those more than 400,000 patients have advanced (≥2+) FMR-CAD. [MitraClip  is the sole percutaneous device commercially approved for treatment of FMR. Over 80,000 patients have undergone mitral repair with the MitraClip device in the past decade. . The dev2) as compared to COAPT (101 ± 34 ml/m2), paralleling increased rates of residual MR. [A key issue with MitraClip is recurrence of MR where recurrent advanced MR is present in over one third of FMR patients treated with MitraClip. –9 Mechandual MR. , 6 TheseFinite element (FE) based computational modeling allows calculation of mitral leaflet stress. For instance, Votta et al. used an FE model of the mitral valve to simulate the effect of edge-edge repair and showed that leaflet stress increases with annular dilatation.  Sturla eThis study employed FE models of the LV + mitral valve based on sheep with FMR after postero-lateral MI , 14 to tSheep used to create the finite element models were treated under a protocol approved by the San Francisco Veterans Affairs Institutional Animal Care and Use Committee , in compliance with the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council.  Adult shAnesthesia for MI, MRI and sacrifice procedures in chronic animals was similar. Briefly, anesthesia was induced with ketamine (20 mg/ kg intravenous) and maintained with isoflurane . Post-operative pain associated with the MI procedure was controlled with buprenorphine (0.01mg/kg) was given subcutaneously every 6 hours for the first 24 hours and then every 8 to 12 hours for 2 more days. In addition, at the conclusion of the MI and MRI procedures, the incision was infiltrated with a long acting local anesthetic (Bupivacaine 0.5% x 10 ml) and ketorolac 30 mg was given intra-muscularly once and as needed for post-operative pain.Fig 1A). Active and passive myocardial constitutive laws were previously described by Guccione et al. [C, and contractility parameter, Tmax, for MI, borderzone and remote regions were inversely calculated by minimizing the difference between modeled and experimentally determined LV volume and regional strain [C and Tmax for MI, borderzone and remote regions were previously reported. [The LV was contoured and meshed as previously described.  On averae et al. , 19 Priol strain  using esl strain  The optieported. Fig 1B). [The mitral leaflets were contoured and meshed as previously described .  Edge choFig 1B).  The mitrFig 1B).  and the The endocardial surface of the FE model was loaded with animal-specific in-vivo LV end-diastolic and end-systolic pressures. During diastole, the mitral leaflets were loaded with MVPG of -4.1 mm Hg in line with MVPG data after MitraClip from Herrmann et al.  During sC, equal to 0.001*C of remote myocardium and Tmax equal to zero. Homogeneous Dirichlet boundary conditions were applied to nodes at the top of the extended base so that the nodes were fixed in the longitudinal axis but allowed to slide in the mitral plane.To isolate the mitral apparatus from boundary condition restrictions, the myocardial elements at the level of the valve were extended 3 elements above the mitral plane. The extended base had diastolic stiffness, Fig 1C). The average body surface area (BSA) of the 5 sheep on which the simulations were based was 1.28±0.04. Given that the normal human BSA is 1.99 [The MitraClip  was simulated by attaching leaflet nodes in a rectangular pattern extending from the centers of the leading edge of the central regions of the anterior and posterior leaflets . Simulation of LV diastole and systole then proceeded.Leaflet nodes were attached using ‘virtual suture’ beam elements  as previously described.  SpecificFig 2).LV volume at early filling was increased by using a pre-inflation step where the LV endocardial surface was loaded with animal-specific LV ED pressure until an increase in LV volume of 20% was achieved. The deformed FE mesh was used as the unloaded geometry of a new ↑LV_VOLUME model. Simulation of virtual MitraClip was then performed using the new ↑LV_VOLUME model . Elements with nodes attached to virtual suture beam elements were excluded to avoid stress concentrations associated with local MitraClip-induced element distortion.Von Mises stress was averaged across anterior and posterior leaflets. Von Mises stress was measured in the one element wide region of elements one element removed from the MitraClip .Green-Lagrange strain was calculated where the reference geometry for strain at ED is the pre-operative early-diastolic filling LV shape.  Err at Esimulations were solved with LS-DYNA  running on a standalone Windows  workstation . Simulations used between 3 and 16 virtual processors depending on resource availability.FE All values are expressed as mean ± standard deviation and compared by repeated measures analysis using a mixed model to test for both fixed and random effects . Models included categorical factors for MitraClip clip size, ↑LV_VOLUME and leaflet region. ED and ES analyses were done separately and in all simulations the animal/ model number was treated as a random variable. Significance was set at p<0.05. Box and whisker plots were constructed with the whiskers at the minimum and maximum of the group data range. All data points in each group are shown as individual points in the plot.All FE simulations finished successfully with an average calculation time of 64.7 ± 24.6 minutes. Linear regression of simulation calculation time  with the number of virtual processors (NCPU) was CalcTime = -4.95 NCPU + 95 and reached an approximate minimum at 8 virtual processors.Fig 3 shows representative regional leaflet stress color maps of the mitral valve before and after MitraClip with complete grasp. Changes in leaflet stress are most apparent at LV end-diastole (ED) , during which stress is concentrated in the clip region and increased stress occurs between the device and the mitral annulus. Leaflet stress was also increased in the peri-MitraClip region at LV end-systole (ES)  although the effect is less pronounced. Color maps from the volume augmented (20% ↑LV_VOLUME) FE models . As shown, end-diastolic leaflet stress adjacent to the device increased in all animals. At baseline, MitraClip increased peri-MitraClip leaflet stress in the anterior mitral leaflet by 544% and in the posterior leaflet by 131% (both p<0.0001)  in the anterior leaflet, and by 5.8% (p = NS) in the posterior leaflet  and 21.1% (p<0.0001) in baseline and LV volume augmented models respectively. Lesser, albeit significant, reductions in LV end-systolic SLAD occurred in both baseline and volume augmented models . The effect of LV size was not significant at ED but was significant at ES (p = 0.03).LV annular diameter, as measured from the septum to the lateral wall (SLAD), before and after MitraClip implantation are shown in Fig 6 shows representative color maps of change in LV end-diastolic myocardial radial strain (Err) after simulated MitraClip with complete grasp. Note the change in Err in the P2 region (white rectangle) with highest intensity in the P2 endocardium. Note also that intensity is increased in the LV volume augmented model.Fig 7 illustrates the quantitative effects of MitraClip on radial strain (Err) in the lateral (P2) sub-valvular myocardium  and endocardium  at end-diastole, and in sub-valvular myocardium at end-systole : As shown, MitraClip increased Err at end-diastole by 138% in sub-valvular myocardium, and by 131% in baseline and LV volume augmented models respectively (both p<0.0001). MitraClip yielded even larger effects on endocardial end-diastolic Err, as evidenced by increases of 230% and 186% in baseline and LV volume augmented models respectively (both p<0.001), corresponding to absolute increments of 0.052±0.035 and 0.044±0.049. Conversely, MitraClip decreased end-systolic Err at ES in lateral sub-valvular myocardium by 41.9% and 45.1% in baseline and LV volume augmented models respectively (both p<0.001) . The effect of LV size was not significant at ED or at ES.Ell) is shown in S1 Fig. The pattern of effect on Ell is similar to that of radial strain but inverted, meaning that longitudinal strain generally decreased post-procedure. Different than Err, the effect of LV size was significant at ED and ES.The quantitative effect of MitraClip on longitudinal strain  and decreased at end-systole (ES). Mechanical effects of MitraClip are augmented by in the enlarged LV, as leaflet stress and Err were further increased in ↑LV_VOLUME models at end-diastole.The principal finding of this study is that MitraClip implantation for FMR increases both end-diastolic and end-systolic mitral leaflet stress in the peri-device region: As a consequence, septo-lateral annular diameter was decreased and Fig 8 illustrates proposed mechanism).Regarding the underlying mechanism of MitraClip action, it should be noted that mitral leaflet stress is a function of leaflet and annular geometry, leaflet material properties, and loading conditions. MitraClip pulls the anterior and posterior leaflet edges together, thus inducing stress on the mitral leaflets that would be expected to increase in proportion to the amount of tissue gathered by the MitraClip . Pantoja et al., did not measure the effect of UA on annular shape but when compared with MitraClip, the magnitude of annular reduction was likely significantly larger and annular reduction extended across the entire posterior annulus.Pantoja et al. studied the effect of UA on procedure related strain in the LV wall and showed that UA significantly increased longitudinal strain in the proximal lateral LV wall.  SpecificErr in LV sub-valvular myocardium. Based on this observation, we anticipate that compared to MitraClip NTR (9 x 5mm), MitraClip XTR (12 x 5mm) will cause even larger leaflet stress concentration and more positive Err at ED and cause an even larger reduction in the SL dimension at ED.MitraClip NTR with both partial and complete grasp was simulated in this study where compared to the partial grasp, the complete grasp had overall larger effect on leaflet stress, SL dimension and The primary limitation of this study is that our calculations were not optimized with experimental data obtained after MitraClip. On the other hand, SL annular dimension at end-diastole decreases between 2.8 to 4 mm in patients with FMR after MitraClip –38 and LSecond, the MR jet location was not measured in the sheep used in the current study.  Three-diFinally, leaflet stresses at ED and ES were examined in the current study, although Rabbah et al. observed that leaflet stress was greatest during peak systole.  Future pFinite element simulations performed in this study demonstrate that MitraClip increases peri-MitraClip leaflet stress at both ED and ES when performed for FMR. Subsequent traction on the mitral annulus causes the SL dimension to decrease and endocardial strain in the adjacent LV wall at ED is increased. Further, mechanical effects of MitraClip on leaflet stress and sub-valvular LV strain are augmented in the enlarged LV.Increased mitral leaflet stress and procedure-related strain in the sub-valvular myocardium may contribute to mitral leaflet and LV remodeling after MitraClip. Future clinical studies are warranted to clinically test device-induced mechanical effects as predictors of procedural success for patients undergoing MitraClip.S1 FigE_ll, after simulated partial and complete grasp MitraClip in the P2 sub-valvular myocardium at end-diastole (A), P2 sub-valvular endocardium at end-diastole (B) and P2 sub-valvular myocardium end-systole (C) respectively. Ell before and after MitraClip is relative to the pre-procedure unloaded state.Longitudinal strain, (TIF)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


We congratulate Wang and colleagues for their study and very successful results . Althoug We are grateful to Iner et al. for their interesting and valuable comments on our paper.Peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) increases the left ventricle (LV) afterload, and LV overload increases wall stress and myocardial oxygen consumption, jeopardising LV recovery in postcardiotomy cardiogenic shock patients . In our


The aim of this study was to identify in asymptomatic patients with repaired tetralogy of Fallot the prevalence and determinants of impaired left‐sided cardiac function and adverse ventricular remodeling and the relation of left ventricular (LV) dysfunction and remodeling with cardiopulmonary exercise capacity.P=0.001; 49% below age‐adjusted fifth percentile for controls), lower LV mass index (P=0.003), lower LV mass/volume ratio (P<0.01), and impaired left atrial function. Right ventricular mass/volume ratio was the best predictor for LV systolic dysfunction and for a lower LV mass/volume ratio. Compared with controls, LV extracellular volume was higher (P<0.001), particularly in female patients, and associated with subnormal peak oxygen consumption (P=0.037). A peak oxygen consumption below the third percentile reference level was more likely with decreasing LV ejection fraction (P=0.008), and lower LV mass index (P=0.024), but independent of right ventricular ejection fraction.In a cross‐sectional study, 103 patients with tetralogy of Fallot  in New York Heart Association class 1, with surgical repair at a median age of 1.1 years, and 63 age‐matched controls were studied. LV, right ventricular function and geometry, LV myocardial extracellular volume (n=57), and left atrial function were quantified with cardiac magnetic resonance. Peak oxygen consumption was measured by a standardized cardiopulmonary exercise test (n=70). Patients with tetralogy of Fallot had lower LV ejection fraction (In New York Heart Association class 1 patients with tetralogy of Fallot, frequent impaired systolic and diastolic LV function, LV adverse remodeling with LV atrophy, a decreased mass/volume ratio, and extracellular matrix expansion suggest cardiomyopathic changes. The best predictor for LV systolic dysfunction was the right ventricular mass/volume ratio. The subnormal peak oxygen consumption indicates that monitoring of LV status may be important for long‐term prognosis. Impaired systolic and diastolic left ventricular (LV) function, adverse LV remodeling with extracellular matrix expansion, reduced cardiomyocyte mass (atrophy), and a decreased mass/volume ratio have been reported in young to middle‐aged patients with tetralogy of Fallot at a median of 14 years after repair, suggesting LV cardiomyopathic changes, despite the absence of any limitations to normal physical activity (New York Heart Association class 1).Markers of LV systolic dysfunction and adverse tissue remodeling (reduced cardiomyocyte mass), measured by cardiac magnetic resonance imaging, were associated with subnormal peak oxygen consumption during cardiopulmonary exercise testing, an important risk predictor in tetralogy of Fallot.This study recommends imaging‐based surveillance of the LV in patients with repaired tetralogy of Fallot to monitor adverse remodeling.Timely initiation of surgical reintervention for pulmonary insufficiency if present, or medical heart failure therapy, may delay progression of adverse remodeling and improve the long‐term prognosis.In tetralogy of Fallot (ToF), the main clinical focus after surgical repair is directed to the right ventricle (RV) .Indeed, a recent study identified LV systolic dysfunction as an outcome predictor for death and ventricular tachycardia in ToF.Cardiac magnetic resonance (CMR) is optimally suited to simultaneously assess adverse RV and LV volumes and function.The goals of the present study were as follows: (1) to determine the prevalence of LV dysfunction in NHYA class 1 patients with ToF and to identify associations between right heart markers of pathologic and LV remodeling; and (2) to determine, in a subset of patients n=70) with cardiopulmonary exercise testing, if LV dysfunction and remodeling have an impact on age‐ and sex‐adjusted peak exercise capacity, a potentially important risk predictor for adverse events in ToF.0 with caThe data that support the findings of this study are available from the corresponding author on reasonable request.The cohort for this prospective cross‐sectional study consisted of consecutive patients with ToF without overt symptoms, who underwent CMR imaging between January 2012 and August 2016. Patients with clinical symptoms of New York Heart Association functional class >1 as well as patients taking cardiac medications, like angiotensin‐converting enzyme inhibitors and β blockers, were excluded. The Institutional Review Board of our hospital approved the study (protocol No. A168/07), and informed written consent was obtained from either the patients or their guardians. Age‐matched healthy controls were recruited for comparison with the ToF cohort among patients scheduled to undergo a clinically indicated, contrast‐enhanced neurological magnetic resonance imaging or an magnetic resonance imaging study to rule out a vascular abnormality within the thorax. All individuals in the control group had a normal CMR examination result and no history of left‐sided heart disease or cardiomyopathy.All CMR studies were performed with a 1.5‐T scanner  using a phased‐array coil for cardiac imaging. In patients aged <7 years, sedation with propofol and midazolam was necessary. Heart rate, oxygen saturation, and noninvasive blood pressure were assessed with a CMR‐compatible monitor . Dedicated CMR software  was used to analyze the images.max), minimal LA volume at mitral valve closure (LAmin), and LA volume immediately before atrial contraction (LAbac). LA volumes and LA functional parameters  were calculated as described previously.max and LAmin, and was divided into LA passive emptying volume and LA contractile volume. LA contractile volume was the difference between LAbac and LAmin, and LA passive emptying volume was the difference between LAmax and LAbac. LA functional parameters were calculated according to the following formulas:Short‐axis cine imaging was performed to measure LV and RV volumes at end systole (ES) and end diastole (ED), mass at ED, and ejection fraction (EF), per standard guidelines.A retrospectively gated, phase‐contrast cine pulse sequence, with through‐plane velocity encoding, was applied to measure flow  in the main pulmonary artery, with the slice positioned ≈1.5 cm above the pulmonary valve. Pulmonary regurgitation was calculated as the fraction of forward flow that returned to the ventricle in diastole.Late gadolinium enhancement (LGE) imaging was performed using the contrast agent gadopentetate dimeglumine , with a contrast bolus of 0.1 mmol/kg. Approximately 15 minutes after contrast administration, LGE images were acquired with an inversion‐recovery–prepared 3‐dimensional gradient echo sequence  adjusted to null normal myocardium) with respiratory navigator technique. The presence and location of LGE was identified qualitatively by signal enhancement within the myocardium. Some patients or their guardians either declined to receive contrast or woke up from sedation and did not receive contrast agent (36%). Heart‐healthy control subjects did not receive any contrast agent, except for 12 subjects who were scanned for a neurological indication.Cardiac T1 measurements were performed using a cine Look‐Locker technique2 max) was measured by a standard exercise test2 max was obtained in mL kg−1 min−1, and expressed as age‐ and sex‐adjusted percentile ranking on the basis of previously published cardiopulmonary exercise testing (CPET) reference data from 548 female and 647 male patients within 4 to 75 years of age.2 max lower than the third percentile levels for a normal reference population.Peak oxygen consumption , and the R language and environment for statistical computing .As most LV parameters in normal controls show a significant association with age, we defined their normal ranges as a function of age. Smooth curves, corresponding to the 5th and 95th percentile levels for LV parameters measured in healthy volunteers, were calculated with generalized additive models for location scale and shape, using a spline for age as single predictor (package “gamlss” in R). As all controls who had ECV measurements in our study were aged <18 years, we used published referenced data2 max (in mL/kg per minute) included age, sex, LV EF, and cardiomyocyte mass index as predictors . (LV mass was not included as simultaneous predictor because of a relatively strong collinearity with cardiomyocyte mass index.) Preliminary analysis suggested that some of the relationships with VO2 max appeared to be nonlinear. Therefore, we used a generalized additive model and represented age, LV EF, and cardiomyocyte mass index by cubic regression splines to account for these nonlinearities. Multivariate logistic regression analysis was used to identify predictors of abnormally low VO2 max.Multivariate regression models were built for LV EF and LV mass/volume ratio, to determine which measures of right‐sided dysfunction were associated with LV dysfunction and LV remodeling. Age, sex, BSA‐indexed RV volumes at ED and ES, RV mass, RV mass/volume ratio, LV/RV mass ratio, and RV peak pressure from a contemporaneous Doppler‐echocardiography examination were considered as predictors. A best model was chosen by step‐wise forward and backward predictor selection, using the Akaike information criterion. Associations between the prevalence of eccentric LV remodeling and continuous RV parameters were analyzed by logistic regression analysis. A multivariate model for VO2 max value.A total of 103 patients with ToF  were studied at 15.1±8.7 years  after surgical repair of ToF. The patient characteristics are summarized in Table r=0.36, P<0.001). Patients with ToF and controls had similar heart rates  and RV mass/volume ratio . Using the categories of LV systolic dysfunction used in the study of patients with ToF by Broberg et al,P=0.002 for Jonckheere nonparametric test for increasing RV mass/volume ratio across ordered categories of LV systolic dysfunction). The association between LV systolic dysfunction and RV mass/volume ratio remained significant in a multivariate model for RV mass/volume ratio, with LV EF and age (P=0.33 for age effect) as simultaneous independent predictors. Figure P=0.002 for Jonckheere nonparametric test). The probability of less than mild LV dysfunction decreased by 0.38:1 for a 0.1 increase of the RV mass/volume ratio (P=0.009).In ToF, LV EF correlated with RV EF . LV mass/volume ratio correlated with RV mass/volume ratio , as shown in Figure r=0.42; P<0.001). Approximately 28% of all patients with ToF had a LV mass/volume ratio below the age‐specific fifth percentile level in healthy controls, as illustrated in Figure LV mass/volume ratio, a parameter characterizing LV remodeling, was significantly lower in patients with ToF than in healthy controls . Total and passive LA EFs were negatively associated with age, unlike in healthy controls, in whom they remained nearly constant.LA volumes and function were decreased compared with controls Table . LAmax, LGE imaging was performed in 65 patients: 62 (95%) of those had LGE at the site of ventricular septal defect patching, 30 (46.1%) showed LGE in the RV outflow tract, and 9 (13.8%) had small spots of LGE that were detected in other areas of the heart but not the LV free wall.P<0.01). Female patients with ToF showed a significantly higher ECV than male patients (P=0.033). Even when the patients with ToF and LGE in the LV were excluded, ECV was still significantly higher compared with controls . For patients with ToF and abnormally low LV EF, ECV was significantly higher in the septum, compared with patients with ToF and LV EF within the normal range (P=0.02). The LV mass index correlated negatively with ECV .Myocardial ECV was obtained in 57 (55%) of 103 patients with ToF, from the time when the T1 sequence was available on the scanner. It was significantly elevated compared with controls  in 20 patients (29%), and there was no significant difference in the proportion of abnormal VO2 max between male and female patients with ToF .CPET results were available for 70 patients with ToF (68%) who reached the anaerobic threshold. VO2 max, impaired LV resting systolic function and adverse LV remodeling were more frequent than in patients with VO2 max above the third percentile level for controls. In univariate logistic regression models, the likelihood of an abnormally low VO2 max increased with lower LV EF  and a lower LV mass index . LV EF and LV mass index remained significant predictors of an abnormally low VO2 max, when RV mass/volume ratio, RV ESV index, and RV EF were each added as additional predictor in these 2 models, suggesting that LV dysfunction increases the likelihood of impaired exercise capacity, independent of the degree of RV systolic dysfunction and remodeling. A comparison of the patients with ToF and abnormally low VO2 max and normal VO2 max showed that they had a lower LV EF  difference for the free wall ECV average between patients with ToF with normal and abnormal VO2 max.In patients with ToF and abnormally low VOF Figure A, a loweF Figure B, and a F Figure C. To fur2 max (in mL/kg per minute), the cardiomyocyte mass had a significant association with VO2 max (P=0.014), with simultaneous adjustment by sex (P=0.06), age (P=0.25), and LV EF (P=0.057). The predicted dependence of VO2 max on cardiomyocyte mass index is shown in Figure In a multivariate generalized additive model for VOEF P=0.05. The prelower‐than‐average RV mass, RV dilation , and a lower RV mass/volume ratio, are associated with a lower LV mass/volume ratio. The diminished LV mass observed in ToF, in combination with the expansion of the ECV in the LV, implies a loss of total cardiomyocyte mass indicative of LV atrophy. LV systolic dysfunction and the loss of LV mass correlated with impaired exercise tolerance, independently of the RV parameters that predict LV remodeling (RV mass/volume ratio) and LV dysfunction (RV ESVi and RV EF). In a multivariate analysis, LV atrophy had a stronger effect on VO2 max than LV EF, suggesting that LV cardiomyocyte mass may be an important parameter for monitoring LV remodeling in patients with ToF, with the advantage, compared with LV EF, that it is not dependent on hemodynamic loading conditions. In light of previous studies,In this study, clinically asymptomatic patients with repaired ToF frequently show left‐sided diastolic and systolic dysfunction and a lower than normal LV mass/volume ratio that is consistent with a previously described pattern of eccentric LV remodeling.Histological studies have shown increased interstitial collagen content in both the RV and LV walls of patients with ToF.ECV was negatively associated with the LV mass index, suggesting that interstitial fibrosis is linked with LV atrophy in ToF. The negative correlation in ToF of ECV with the LV mass index is opposite to a positive correlation observed in pathological hypertrophy resulting from hypertensive heart diseaseApproximately two thirds of patients with ToF had mild‐to‐moderate LV systolic dysfunction, and in nearly half of them the LV EF was below the age‐adjusted fifth percentile for normal controls Table . This is2 max sets in for LV cardiomyocyte mass indexes <≈39 g/m2 in male patients and <≈30 g/m2 in female patients, indicative for LV atrophy. For comparison, assume a healthy 20‐year‐old man with a myocardial ECV fraction of 0.25 ×LV mass index, would range from ≈45 to 70 g/m2. The observed decline of VO2 max around a level of 39 g/m2 is, therefore, consistent with the expected threshold for LV atrophy on the basis of published reference values for LV mass index. A higher ECV, indicative of diffuse fibrosis, would lower this threshold further. The investigated parameters of LV dysfunction  may, therefore, have a functional significance for predicting impaired exercise capacity that goes beyond the changes in RV volumes and function. In the statistical analysis, the significance of LV EF for prediction of impaired exercise capacity remained with adjustment by RV parameters, equally suggesting that LV EF in this context should not be interpreted as surrogate for RV markers of dysfunction. In contrast to previous studies,P<0.001) correlation between RV EF and LV EF was observed in our study , whereas our cohort only included asymptomatic patients with ToF. In adults with acquired heart disease and compromised RV EF,The subclinical LV abnormalities reported in our study  may contribute to the reported risk of later clinical left‐sided heart failure and cardiac death in ToF.z score <−2.0), an RV mass/volume ratio ≥0.3 g/mL, and history of atrial tachyarrhythmias; however, more important, RV EF was not a predictor. These findings in an older population  with signs of overt heart failure underscore the potential importance of LV systolic dysfunction for adverse outcomes. Bokma et alValente et al previously investigated in patients with ToF the association between markers of RV and LV remodeling/dysfunction and outcome (death and ventricular tachycardia).Diastolic dysfunction may be one of the earliest manifestations of adverse LV remodeling in ToF. We examined LA function by CMR cine volumetry,The results of this study should be viewed in the context of its design. Given that this is a cross‐sectional study, we cannot relate causes and effects in the interplay of LV function and structure, intrinsic tissue‐level alterations (by ECV), RV‐LV interdependence, diastolic properties (as reflected by LA function), or vascular stiffness. Patients aged <7 years (15% of ToF cohort) were sedated during the CMR studies, which may have depressed cardiac function. The statistical significance of the main findings  and had a lower body mass index (18.4±4.82 versus 21.9±4.7 kg/m2), but showed no difference in sex distribution.The availability of CPET for only a subset of 70 (68%) of patients with ToF may have introduced a selection bias in the analysis of the associations between abnormally low VO2 max, an important risk predictor in ToF.This multiparametric CMR study on LV remodeling in asymptomatic patients with ToF at a median of 14 years after surgical repair revealed the following: (1) frequent (49%) impaired systolic function over the full age range, abnormal diastolic relaxation, a decreased LV mass, and interstitial matrix expansion (as reflected by ECV), which are all evidence of adverse LV remodeling and a cardiomyopathic phenotype (the best predictor for LV systolic dysfunction was the RV mass/volume ratio); and (2) CMR markers of LV systolic dysfunction and adverse tissue remodeling (reduced cardiomyocyte mass) correlated with subnormal VOTherefore, early surgical reintervention for pulmonary insufficiency if present, or medical heart failure therapy, both guided by CMR‐guided surveillance of the LV, may delay progression of adverse remodeling and improve the long‐term prognosis.http://www.kinderherzen-wollen-leben.de/).This work was supported by a postdoctoral fellowship grant (6619‐10‐0) for Dr Andrade from the Coordination of Improvement of Higher Education Personnel of Brazil and by a research grant from the foundation “Kinderherzen–wollen‐leben e.V.” for Dr Pham (None.


Majority of the incidentally discovered adrenal masses, called adrenalincidentaloma (AI), are nonfunctioning adrenal adenomas. The appropriatemanagement of AI is still a matter debate, so it is necessary to investigatetheir associated morbidity. However, data regarding morphological andfunctional cardiac alterations are limited in this group.In this study, we aimed to assess cardiac structural and functionalcharacteristics and atrial conduction properties in patients withnonfunctioning AI.Thirty patients with nonfunctioning AI and 46 properly matched controlsubjects were included in the study. After hormonal and biochemicalanalysis, all participants underwent transthoracic echocardiography toobtain systolic and diastolic parameters of both ventricles, in addition toatrial conduction times by tissue Doppler echocardiography. Data wereanalyzed with Statistical Package for the Social Sciences  statistics, version 17.0 for Windows. P < 0.05 wasconsidered statistically significant.Left ventricular (LV) mass index and LV myocardial performance index weresignificantly increased in AI group. Among atrial conduction times, bothintra- and interatrial electromechanical delays were significantly prolongedin patients with nonfunctioning AI. Other laboratory and echocardiographicfindings were similar between groups.Our study revealed that intra- and inter-atrial conduction times wereprolonged, and LV mass index was increased in patients with nonfunctioningAI. These findings may be markers of subclinical cardiac involvement andtendency to cardiovascular complications. Close follow-up is necessary forindividuals with nonfunctioning AI for their increased cardiovascular risk. The presence of AI has been proposed as anew cause of metabolic syndrome and reported to increase cardiovascular diseaserisk. The burden of disturbances showed diversity from impaired glucose tolerance toincreased epicardial fat thickness and intima-media thickness of common carotidarteries.2-6 However, data regarding morphological and functional cardiacalterations are still limited in this particular group.Adrenal incidentaloma (AI) is defined as an adrenal mass, generally discovered inradiological interventions for indications other than adrenal disease. The classicdefinition excludes patients with clinically overt adrenal hormone secretion, andthose with concurrent malignancy, known as metastasis to the adrenals. Theprevalence of adrenal masses in general population has been reported to be as highas 6% at autopsy, and 2.5-4.2% on evaluation of abdomen and thorax by computerizedtomography (CT).7 Several studies report that atrial EMD measured by TDE is avaluable parameter to predict new onset AF or recurrence of AF.8-11Atrial fibrillation (AF) is one of the most common arrhythmias observed in clinicalpractice. Several electrocardiographic and echocardiographic markers reflectingelectrophysiological and electromechanical abnormalities of atria prone to developAF have been studied with the aim of early identification of patients susceptible todevelop AF. Atrial electromechanical delay (EMD) has been defined as the temporaldelay between the onset of electrical activity and the mechanical activation ofatrial myocardium. Tissue Doppler echocardiography (TDE) is a simple, noninvasiveand reliable method to measure atrial EMD.5,12 The aim of this study was to assess intra- and inter-atrialconduction times along with cardiac structural and functional characteristics inpatients with nonfunctioning AI.There are few studies evaluating cardiac functions in patients having nonfunctioningAI, but to our knowledge data concerning atrial electromechanical properties arelacking.All subjects who were referred to the Department of Endocrinology and Metabolismof Kahramanmaras Sutcu Imam University, in Kahramanmaras, Turkey, withincidentally discovered adrenal tumors between March 2014 and November 2015 wererecorded (n = 82). The study was approved by local Research Ethics Committee ofthe institution in compliance with the Declaration of Helsinki. All of theparticipants gave written consent.magnetic resonanceimaging (MRI) scan to confirm the diagnosis. Adrenal adenoma wasdiagnosed if the following criteria were met:At the first visit, all subjects underwent a CT or tumor size less than 4.0 cm;regular shape with well-defined margins;13homogenous and attenuation value of 10 or less Hounsfield units onunenhanced CT scan, and 30 or less Hounsfield units on enhanced CTscan.14Moreover, patients were given a diet free of food containing phenolic acid forfive days. Then, 24-hour urine specimens were collected for metanephrine andnormetanephrine analyses. Pheochromocytoma was defined as elevated levels ofurinary normetanephrine  and/or urinarymetanephrine .13 Age and sex matched 46 subjects withoutclinical suspicion of hypercortisolism, with normal DHEAS level , suppressed 1 mg DST (≤ 1.8µg/dl) and without adrenal mass on abdominal ultrasonography were takenas the control group. Blood pressure measurements of all subjects were takenfrom right arm in the sitting position after 5 minutes of resting. Height(meter) and weights (kg) of all participants were recorded, and body mass index was calculated.After confirming the presence of adrenal adenoma, detailed physical examinationand basal hormonal and dynamic tests were performed. Among participants, 30patients having nonfunctional adrenal adenomas were included in the study.Totally 52 patients with uncompleted tests or hormone-secreting tumors - highlevels of dehydroepiandrosterone sulphate (DHEAS), hyperaldosteronism, Cushingsyndrome (CS), pheochromocytoma - and patients having large adrenal tumors(>4 cm) with irregular borders and invasion to adjacent structures raisingthe suspicion of malignancy were excluded. Additionally, patients with knownmalignancies, coronary artery disease, valvular heart diseases,cardiomyopathies, thyroid dysfunction, chronic renal failure, liver failure,previous surrenal or hypophysial intervention or patients taking steroids werenot included in the study. In an attempt to determine the hormonal activity ofadrenal tumors, blood samples were collected at 8.30 am to analyze sodium (Na),potassium (K), adrenocorticotropic hormone (ACTH), DHEAS and plasma cortisollevels. For exclusion of CS, 1 mg dexamethasone suppression test (DST), the mostcommon screening test for CS, was performed to the patients. The suppression inovernight DST was adequate when morning cortisol level fell below 1.8µ/dl. Blood samples for plasma renin and aldosterone measurements werecollected after at least 4-6 hours of nocturnal resting, following two hours ofstanding or wandering, and after 15 minutes of resting, respectively. Plasmaaldosterone concentration (PAC)/plasma renin activity (PRA) ratio was used asthe screening test to exclude primary aldosteronism. PAC/PRA ≤ 20 valueswere accepted as normal.15-17All participants were performed transthoracic echocardiography , including two-dimensional,M-mode, pulsed, and color flow Doppler examinations by the same experiencedcardiologist blinded to the clinical status of the subjects. Recordings weremade on left lateral decubitus position by using standard parasternal, apical,and subcostal views. Left atrial dimension, left ventricular (LV) end-diastolicand end-systolic diameters, diastolic thickness of ventricular septum andposterior wall were measured from M-mode in parasternal long axis view accordingto the criteria of the American Society of Echocardiography guidelines. Theearly (E-wave) and late diastolic (A-wave) velocities of mitral inflow weremeasured from apical four chamber view with pulsed Doppler echocardiography byplacing the sample volume at the tips of mitral leaflets, and E/A ratio wascalculated. Ejection fraction was estimated by Simpson’s rule. LV mass wascalculated by Devereux formula and indexed to the body surface area.15 Systolicpulmonary artery pressure (sPAP) was obtained from the maximum velocity of theregurgitant tricuspid jet, and pulmonary acceleration time (PAT) was measured asthe time between the onset and peak of pulmonary velocity obtained by pulsedDoppler recording.18Right ventricular (RV) morphological and functional parameters including rightatrial dimension, RV diameter, and tricuspid annular plane systolic excursion(TAPSE) were measured according to the American Society of Echocardiographyguidelines.TDE was performed with transducer frequencies of 3.5-4.0 MHz using a 5 mm pulsedDoppler sample volume. Spectral Doppler signal filters were set to obtain aNyquist limit of 15 to 20 cm/s with minimal optimal gain settings. The sweepspeed was set at 50 to 100 mm/s. A single lead electrocardiogram (ECG) wasrecorded simultaneously during measurements. In the apical four chamber view,the sample volume was subsequently placed at the level of LV lateral mitralannulus, septal mitral annulus and RV tricuspid annulus. The sampling window waspositioned as parallel as possible to the myocardial segment of interest toobtain the optimal angle of imaging. Time intervals from the onset of P wave onthe surface ECG to the beginning of the A wave (PA) representing atrial EMD wereobtained from lateral mitral annulus, septal mitral annulus, and tricuspidannulus and named PA lateral, PA septum and PA tricuspid, respectively. Thedifference between PA lateral and PA tricuspid was defined as inter-atrial EMD, the difference between PA lateral and PA septum wasdefined as intra-atrial EMD . Peak systolic (Sm), earlydiastolic (Em), late diastolic (Am) velocities, and isovolumic contraction time, isovolumicrelaxation time , and ejection time  were obtained from mitral and tricuspid annulus. Em/Am ratio for bothventricle and E/Em for LV were calculated. The myocardial performance index(MPI), a noninvasive Doppler measurement of global ventricular functionincorporating both systolic and diastolic function, was calculated by theformula of (ICTm+IRTm)/ETm for both ventricles.w/√2n(m-1)) = confidence in theestimate1,96*.Intraobserver variability was assessed in 20 subjects randomly chosen from theparticipants, and the echocardiographic measurements were repeated under thesame basal conditions. Simple random sampling method was used in the selectionof 20 subjects. 2test for categorical variables. Mean values of continuous variables werecompared between groups using Independent samples t-test or Mann-Whitney U-test,according to whether normally distributed or not. Correlation between continuousvariables was evaluated by Pearson correlation tests. A linear regressionanalysis and generalized linear models were used to identify predictors ofatrial EMD. P < 0.05 was considered statistically significant.Data were analyzed with Statistical Package for the Social Sciences  statistics, version 17.0 for Windows. Shapiro-Wilktest was used to test the normality of distribution for continuous variables.Continuous variables were expressed as means ± standard deviation.Non-normal distributed variables were expressed as Median and quartiles(1.Quartile-3.Quartile). Categorical data were presented as numbers andpercentages. Difference between groups was detected using χClinical and laboratory data of the study groups are given in Conventional echocardiographic parameters were shown in Comparison of tissue Doppler parameters and atrial conduction times were demonstratedin 2= 3.810, p = 0.049) , mitral E/A ratio , and RV Em/Am ratio , and positively correlated with LVmass index , left atrial diameter , age  and systolic blood pressure . Intra-atrialEMD was positively correlated with post DST cortisol level , LVmass index , age  and systolic bloodpressure , and negatively correlated with mitral E/A ratio . Multivariate relationships of inter- and intra-atrial EMD withclinical parameters revealed that changes in post DST cortisol levels affectedintra-atrial EMD significantly  . We alsoThis is the first tissue Doppler echocardiographic study evaluating abnormalities ofatrial conduction together with cardiac structure and function in nonfunctionaladrenal incidentalomas. We obtained two important findings:LV mass increased significantly;Intra- and inter-atrial conduction times were delayed significantly inthese patients.6,19 It has also been shown previouslythat Cushing syndrome causes cardiac structural changes associated with LVdysfunction.20,21 However, it is still a matter of debate whether nonfunctionalAI increases the risk of cardiovascular disease and whether this type of adrenaltumor has some degree of autonomous adrenal function. In this study, we obtainedsome indirect evidence of subtle cortisol autonomy and cardiovascular risk inpatients with nonfunctioning AI. There are few studies analyzing cardiac morphologyand function in nonfunctional AI. Ermetici et al.12 reported the presence of LV hypertrophy and LVdiastolic dysfunction in patients with nonfunctional AI.12 Iacobellis et al.5 showed increased epicardial fat thickness and LVmass by transthoracic echocardiography in these subjects.5 Similarly, we found that LV mass index was increasedsignificantly in patients with nonfunctional AI compared to the control group. Theimpact of LV hypertrophy on cardiac mortality and morbidity has been understoodincreasingly.16 It hasbeen suggested that cortisol production by AI may have a broad spectrum, rangingfrom normal to various degrees of excess daily production rate, and this may not bedetectable by standard endocrine work-up.12 In our study, basal cortisol levels of the groups weresimilar, but post DST cortisol levels were significantly elevated , and DHEAS levels were significantly reduced  in nonfunctioning AI group. Additionally, post DSTcortisol level was correlated with LV mass index. According to these findings, wespeculated that subtle cortisol autonomy of adrenal adenoma might play a role incardiac hypertrophy.It is well known that overt cortisol excess, as in Cushing syndrome, may lead tosystemic complications responsible for increased cardiovascular risk  and cardiovascular complicationssuch as coronary heart disease and congestive heart failure.Myocardial performance index is a parameter calculated from tissue Dopplerechocardiographic measurements, and predicts both systolic and diastolic ventricularfunction. In our study, LV MPI was found to be increased in patients with AIindicating impaired global LV function. This impairment may be attributed largely tothe impairment of LV diastolic function, because the predictors of LV systolicfunction such as LV EF and LV Sm were similar in both groups.Considering structural and functional parameters of RV, decreased RV Em/Am ratiomight indicate the tendency to impairment of RV diastolic function. PAT was alsoshortened, indicating increased pulmonary vascular resistance in patients withAI.22 It has been shown that impaired atrial conduction is anindependent and strong predictor for development and recurrence of AF, and TDE is auseful and reliable technique to evaluate atrial electromechanicalproperties.7-9 Numerous studies demonstrated that atrial conduction time wasprolonged in various diseases including obesity, thyroid diseases, chronicobstructive lung diseases, non-alcoholic fatty liver disease, acromegaly anddiabetes mellitus (DM).23-28Cushing disease is associated with many cardiovascular risk factors, includingglucose intolerance, hypertension, LV hypertrophy, central obesity and metabolicsyndrome, and may lead to cardiovascular events such as coronary heart disease,heart failure and arrhythmias.21So, we hypothesized that AI might be associated with cardiac structural andfunctional changes, and increased risk of AF. Earlier studies showed increasedepicardial fat, increased LV mass and LV diastolic dysfunction in AI similar to ourresults.5,12 However, they did not study atrial conduction properties inthis patient group.Atrial fibrillation is the most common arrhythmia encountered in clinical practice,and associated with significant mortality and morbidity due to hemodynamicimpairment and thromboembolic events. Impaired atrial conduction is an importantstep in the pathophysiology of AF. Atrial conduction times can be evaluated by bothinvasive  and noninvasive (P wave dispersion on ECG andEMD on echocardiography) methods.4-6,13,29Detection of prolonged atrial EMD in these patients may be an earlier sign of atrialdysfunction preceding AF.Therefore, this study showed for the first time that both intra- and inter-atrial EMDwere impaired in patients with nonfunctioning AI. Moreover, atrial EMD wascorrelated significantly with post DST cortisol level, ACTH level, LV mass index, LVdiastolic dysfunction, age and systolic blood pressure. Post DST cortisol level wasan important predictor of intra-atrial EMD, such that 1 µg/dl increase inpost DST cortisol level caused the prolongation of intra-atrial EMD by 4.752 msec.We may explain these findings by a few mechanisms. First, subtle cortisol excretioncan affect cardiac structure and function as mentioned previously, which in turn issupposed to have detrimental effects on atrial conduction. Secondly, AI and AF sharecommon metabolic risk factors such as increased blood pressure, insulin resistance,endothelial dysfunction and obesity. Lastly, low-level but long-standing subtlecortisol excretion may have direct toxic effect on myocardium by glucocorticoidreceptors leading to myocardial fibrosis.The major limitation of the study was the relatively small number of the subjectsin adenoma group, besides the inability to define the length of the diseaseowing to the lack of overt clinical features. Finally, our study lacks long-termfollow-up data, since it is a cross-sectional study. The patients could not befollowed for future arrhythmic episodes to see whether the ones with prolongedatrial EMD develop AF.Our study revealed that intra- and inter-atrial conduction times were prolonged andLV mass index was increased in patients with nonfunctioning AI. These findings maybe markers of subclinical cardiac involvement and tendency to cardiovascularcomplications. Thus, individuals diagnosed to have nonfunctioning AI should befollowed up closely for their increased cardiovascular risk.


This study sought to determine the incidence and prognostic significance of persistent iron in patients post–ST-segment elevation myocardial infarction (STEMI).The clinical significance of persistent iron within the infarct core after STEMI complicated by acute myocardial hemorrhage is poorly understood.2* (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping was performed at 2 days and 6 months post-STEMI. Myocardial hemorrhage or iron was defined as a hypointense infarct core with T2* signal <20 ms.Patients who sustained an acute STEMI were enrolled in a cohort study . Cardiac magnetic resonance imaging including T2* maps at 2 days and 6 months post-STEMI; 74 (36%) patients had myocardial hemorrhage at baseline, and 44 (59%) of these patients had persistent iron at 6 months. Clinical associates of persistent iron included heart rate (p = 0.009), the absence of a history of hypertension (p = 0.017), and infarct size (p = 0.028). The presence of persistent iron was associated with worsening left ventricular (LV) end-diastolic volume  and worsening LV ejection fraction . Persistent iron was associated with the subsequent occurrence of all-cause death or heart failure  and major adverse cardiac events  .A total of 203 patients  had evaluable TNCT02072850)Persistent iron at 6 months post-STEMI is associated with worse LV and longer-term health outcomes. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI];   Myocardial hemorrhage Myocardial hemorrhage is a result of severe microvascular injury, with extravasation of erythrocytes secondary to loss of endothelial integrity 2* (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping We aimed to determine the incidence of persistent iron in a large cohort of STEMI survivors using contemporary TWe hypothesized that persisting iron would: 1) be associated with markers of the initial severity of STEMI; 2) present with distinct clinical characteristics when compared with resolved iron; 3) be associated with adverse myocardial remodeling; and 4) be associated with a worse prognosis in the longer term.The full methodology has been reported previously Cardiac magnetic resonance (CMR) imaging analysis was performed on a Siemens workstation . Left ventricular (LV) volumes and ejection fraction were assessed using computer-assisted planimetry .2* image and then copied onto color-coded spatially co-registered maps -weighted raw image with an echo time of 55 ms were planimetered and then copied to the map 2) >2 SD from remote myocardium LV contours on the last corresponding TThe territory of infarction was quantified using computer-assisted planimetry and was expressed as a percentage of LV mass Myocardial salvage was calculated by subtraction of percentage of infarct size from percentage of myocardial edema Adverse remodeling was defined as an increase in LV end-diastolic volume at 6 months from baseline by 20% or more We pre-specified adverse health outcomes that are implicated in the pathophysiology and natural history of STEMI. The primary composite outcome was all-cause death or first heart failure event  following the 6-month CMR scan. The secondary composite outcome was major adverse cardiac events (MACE).The full statistical methods are reported in the Of 343 patients with STEMI referred for emergency percutaneous coronary intervention, 300 underwent serial CMR, 2.2 ± 1.9 days and 6 months after hospital admission. A total of 203 patients were included in the final analysis. The flow diagram for the study is shown in 2* data (n = 203) are shown in The characteristics of patients with paired evaluable TA total of 74 (36%) patients had acute myocardial hemorrhage, and 44 (59%) of these patients had evidence of persistent iron at 6 months. No patients had de novo myocardial hemorrhage between the 2-day and 6-month scans.Compared with patients with resolved hemorrhage from baseline, patients with persistent iron were less likely to have a history of hypertension, and they had higher heart rates at presentation . The culCMR findings were ascertained during the index hospitalization and at 6 months. The CMR findings are summarized in The mean size of hemorrhage at baseline was 26.9 ± 15.2% of infarct size. All patients with acute myocardial hemorrhage had microvascular obstruction.2 signal in the infarct zone at baseline  reduced in size from baseline to follow-up  .2* values within the infarct zone were lower at 6 months in patients with persisting iron . Additionally, patients with persisting iron had higher infarct zone T2 values than patients without acute hemorrhage and patients with resolved iron collectively . There was no difference in T2 values within the infarct zone in patients with persisting iron compared with patients with resolved iron  patients. The median duration of follow-up was 1,457 days . All-cause death or heart failure following the 6-month assessment occurred in 14 (7%) patients, including 4 noncardiovascular deaths, 4 cardiovascular deaths (n = 2 sudden deaths), 1 undetermined cause of death, and 5 heart failure episodes . Persistent iron was associated with the occurrence of all-cause death or heart failure  .Figure 2MACE following the 6-month assessment occurred in 13 (6%) patients, including 3 cardiovascular deaths (2 sudden deaths), 5 heart failure episodes , 4 non-STEMIs, and 1 STEMI.Persistent iron was associated with the occurrence of MACE  .Associations with persistent iron and health outcome were not independent of the initial size of the infarct.2* mapping, after acute myocardial hemorrhage in a cohort of unselected patients with STEMI.We present a large investigation of persistent iron within the infarct core, as revealed by TThe main findings are as follows: 1) 36% patients had myocardial hemorrhage at baseline, and 59% of these patients had evidence of persistent iron at 6 months; 2) de novo myocardial hemorrhage did not occur after the 2-day CMR scan; 3) clinical associates of persistent iron included patients’ characteristics , hemodynamic features at presentation (heart rate), neutrophil count, and electrocardiographic, angiographic and imaging measures of STEMI severity ; 4) higher heart rate, absence of hypertension, and larger initial infarct size differentiated patients who had persisting iron from patients with resolution of iron; 5) persisting iron was associated with increasing LV end-diastolic volume and decreasing LV ejection fraction at 6 months; and 6) persisting iron was associated with an approximately 4-fold increase in the likelihood of all-cause death or heart failure and a 3-fold increase in the likelihood of MACE. Taken together, these findings identify persistent iron residues as a mechanistic explanation of LV remodeling and worsening function . Potenti2* relaxation time returned to normal by 6 months post-STEMI, a finding implying that persistent iron is rare, whereas more recent studies indicated that persistent iron may be much more common 2* mapping methods, which have improved sensitivity and image quality.Our analysis builds on the results of other studies Our results reveal that a history of hypertension may have a protective effect on the persistence of iron. In addition, a diagnosis of hypertension was associated with increasing LV ejection fraction. This is an unexpected finding, given that previous studies showed that hypertension is associated with myocardial hemorrhage acutely Bulluck et al. 2 infarct zone signal in patients with persisting iron; however, the number of patients with resolved iron in their cohort was small (n = 2). Further, none of the patients in the study by Kali et al. 2 in the infarct zone at 6 months was higher in patients with acute myocardial hemorrhage, but no differences were observed in those patients with persistent iron compared with those with resolution  rather than a full LV stack, and therefore minor degrees of hemorrhage could have been missed. However, imaging positions were prescribed on anatomic landmarks, and scans were undertaken in the same laboratory, thus improving our ability to select the same matched slice positions between scans. The T2* acquisition was associated with imaging artifacts that limited the quantification of hemorrhage and iron in some patients. Future improvements to T2* mapping could include the use of high-pass filtered processing Our study lacks pathological correlation of the imaging results. Further, our results do not permit mechanistic interpretation regarding whether inflammation is the primary driver of persistent iron, or alternatively, persistent iron may reflect a defect in macrophage-mediated clearance of hemoglobin degradation products. As a result of time constraints imposed on the CMR examination, the TPerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Myocardial hemorrhage that occurs acutely after STEMI can persist as infarct core iron in the long term in approximately 3 in 5 patients. Persistent iron is predictive of worsening LV function and volumes, all-cause death or heart failure, and MACE in the longer term.COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: The persistence of myocardial iron can be predicted on the basis of the initial severity of the myocardial infarction. In patients with acute myocardial hemorrhage, repeat CMR at 6 months may be useful for risk stratification. Patients who present with more severe infarcts may be targeted with novel treatments, such as intracoronary thrombolysis. Further investigation is warranted.TRANSLATIONAL OUTLOOK: Survival analysis was limited by the small number of events (n = 14). Therefore, the results are hypothesis generating.Persistent iron within the infarct core is common (about 3 in 5) in patients with myocardial hemorrhage early post-STEMI. Persistent iron is predictive of worsening LV function and volumes, as well as all-cause death or heart failure and MACE in the longer term.


Complete and simplified Selvester QRS score have been proposed as valuable clinical tool for estimating myocardial damage in patients with ST-elevation myocardial infarction (STEMI). We sought to comprehensively compare both scoring systems for the prediction of myocardial and microvascular injury assessed by cardiac magnetic resonance (CMR) imaging in patients with acute STEMI.In this prospective observational study, 201 revascularized STEMI patients were included. Electrocardiography was conducted at a median of 2 (interquartile range 1–4) days after the index event to evaluate the complete and simplified QRS scores. CMR was performed within 1 week and 4 months thereafter to determine acute and chronic infarct size (IS) as well as microvascular obstruction (MVO).Complete and simplified QRS score showed comparable predictive value for acute (area under the curve (AUC) = 0.64 vs. 0.67) and chronic IS (AUC = 0.63 vs. 0.68) as well as for MVO (AUC = 0.64 vs. 0.66). Peak high sensitivity cardiac troponin T (hs-cTnT) showed an AUC of 0.88 for acute IS and 0.91 for chronic IS, respectively. For the prediction of MVO, peak hs-cTnT represented an AUC of 0.81.In reperfused STEMI, complete and simplified QRS score displayed comparable value for the prediction of acute and chronic myocardial as well as microvascular damage. However, both QRS scoring systems provided inferior predictive validity, compared to peak hs-cTnT, the clinical reference method for IS estimation. In survivors of acute ST-elevation myocardial infarction (STEMI), the severity of myocardial damage is of major prognostic relevance . CardiacPrevious studies have documented the capability of different electrocardiographic (ECG) markers for prognosis assessment after STEMI . The SelBoth QRS scoring systems have been shown to correlate with the extent of myocardial damage , 7. HoweThe present investigation aimed to evaluate a direct comparison of complete and simplified QRS score as well as in comparison with the clinical reference method peak hs-cTnT for the prediction of CMR-derived myocardial damage in a cohort of STEMI patients treated with primary percutaneous coronary intervention (pPCI).2, Killip class > II and any contraindication to CMR examination . Furthermore, patients with bundle branch or fascicular block were excluded.In this single-centre prospective observational study, we included 201 STEMI patients admitted to the coronary care unit of Innsbruck University Hospital. The flow chart of the present study is presented in Fig. A standard 12-lead surface ECG  was conducted at discharge, at a median of 2 days (Interquartile range [IQR 1–4] after STEMI. Complete (54-criteria/32-point)  SelvesteAll CMR scans were performed on a 1.5-T MR imaging unit  at 3 days (IQR 2–4) as well as 127 days (IQR 121–143) after reperfused STEMI. The detailed imaging and post-processing protocol of our research group was published in detail previously . In briep-value of < 0.05 in univariable analysis were further included in multivariable analyses. Cut-offs for both QRS scores and large IS were defined by the median of the present cohort. For all analyses, a two-tailed p-value of < 0.05 was considered as statistically significant.IBM SPSS Statistics 24.0  and MedCalc Version 15.8  were used for statistical analyses. Continuous variables were expressed as median with corresponding IQR. Categorical variables were presented as absolute numbers with corresponding percentages. Chi-square test was used to assess differences in categorical variables. Differences in continuous variables between two groups were evaluated by Mann–Whitney U-test. Receiver operating characteristic (ROC) curve analysis was applied to evaluate area under the curve (AUC) for the prediction of acute as well as chronic IS and MVO. AUC values were compared according to a method published by DeLong et al. . For mulWe included 201 STEMI patients undergoing pPCI with a median treatment delay of 194 (IQR 128–378) minutes. The mean age of the overall cohort was 56 (IQR 50–67) years. The baseline characteristics are provided in detail by Table p = 0.001), showed higher heart rate (p = 0.041), higher hs-cTnT levels (p < 0.001), larger IS in acute (p = 0.004) and chronic (p = 0.008) setting and higher presence of MVO (p = 0.020).Patients with complete QRS scores > median of 12 points were older (p = 0.044), had higher rates of anterior infarct localisation (p < 0.001), higher hs-cTnT levels (p < 0.001), larger IS in acute (p = 0.001) and chronic (p = 0.003) setting and higher presence of MVO (p = 0.013).Patients with simplified QRS scores > median of 4 points were older (p = 0.004), presented with higher body mass index levels (p < 0.001) as well as chronic (p < 0.001) IS and MVO (p < 0.001). AUC values of both QRS scoring systems and hs-cTnT are presented in detail by Table p = 0.001; AUC = 0.67, 95% CI 0.59 to 0.74, p < 0.001, respectively), chronic IS  and MVO . Peak hs-cTnT resulted in a higher AUC for the prediction of acute  and chronic IS  as well as for the prediction of MVO  (Fig. Univariable and multivariable associations between both QRS scoring systems as well as hs-cTnT and myocardial damage are summarized in Table This is the first CMR study evaluating a direct comparison of the complete and simplified QRS scoring system as well as in comparison with hs-cTnT for the prediction of myocardial damage in STEMI patients undergoing pPCI. The major findings of the present study can be summarized as follows: Complete and simplified QRS score showed comparable predictive value for acute and chronic IS estimation as well as MVO. However, peak hs-cTnT showed higher predictive value for the assessment of myocardial damage. Taken together, both scoring systems could not show any benefit regarding infarct severity assessment after reperfused STEMI in the era of hs-cTnT.The extent of myocardial necrosis is one of the strongest determinants of clinical outcome in STEMI patients , 15. ECGBesides IS, microvascular injury emerged as strong predictor of adverse cardiovascular events after STEMI , 28, 29.Limitations of the present study have to be declared. Firstly, we included relatively stable STEMI patients with Killip class < III in order to perform high-quality CMR imaging. Therefore, these data may not be generalizable for patients in worse clinical condition. Nevertheless, the majority of STEMI patients represent with Killip class < III . SecondlComplete and simplified Selvester QRS score showed comparable predictive value for the assessment of CMR derived IS and MVO in reperfused STEMI. However, compared to peak hs-cTnT, the clinical reference method for the assessment of myocardial damage, both QRS scoring systems revealed inferior predictive value.


To compare the robustness of native T1 mapping using mean and median pixel-wise quantification methods.n = 26) or abnormal heart function (n = 31). Statistical normality of pixel-wise T1 was tested on each myocardial segment and mean and median segmental T1 values were assessed.Fifty-seven consecutive patients without overt signs of heart failure were examined in clinical routine for suspicion of cardiomyopathy. MRI included the acquisition of native T1 maps by a motion-corrected modified Look-Locker inversion recovery sequence at 1.5 T. Heart function status according to four established volumetric left ventricular (LV) cardio MRI parameter thresholds was used for retrospective separation into subgroups of normal (p < 0.001) for the respective 43/42% non-normally distributed segments. Heart function differentiation between two patient groups was significant in 14 myocardial segments (p < 0.001–0.040) by median quantification compared with six (p < 0.001–0.042) by using the mean. The differences by median quantification were observed between the native T1 values of the three coronary artery territories of normal heart function patients (p = 0.023) and insignificantly in the abnormal patients (p = 0.053).Segments with normally distributed pixel-wise T1 (57/58%) showed no difference between mean and median quantification in either patient group, while differences were highly significant  contains supplementary material, which is available to authorized users. Pre-contrast T1 relaxation time, the parameter at stake in native T1 mapping, has shown its potential for identifying myocardial tissue abnormality –7. NativIn measuring cardiac T1 value, numerous studies showed normal native T1 variation on different myocardial regions , 16–19. In liver and heart iron deposition assessment by T2* mapping, pixel-wise median quantification produced lower observer variability compared with mean quantification  and loweThis retrospective analysis was conducted on magnetic resonance imaging (MRI) data acquired from May until October 2015 with approval by the hospital review board waiving the requirement of informed consent. MRI including (native) T1 mapping sequences was used to evaluate 145 consecutive patients examined in clinical routine for suspicion of cardiomyopathy. Patients with overt signs of heart failure, i.e. LGE pattern , irregular heartbeat or myocardial wall, and cavum thickening, were excluded. The remaining 57 patients were divided into two groups with either normal or abnormal functional heart magnetic resonance (MR) parameters. Normal heart function was defined as three of four MR parameters (i.e. left ventricle (LV) end-diastolic volume, LV end-systolic volume, stroke volume, and ejection fraction) being within the normal MR parameter ranges and the fourth still within the border line of normality as defined by Kawel-Boehm et al .All MR scans were performed on a 1.5-T whole-body scanner . Functional heart MR parameters were acquired by performing cine imaging steady-state free precession images with echo time (TE) 1.1 ms, repetition time (TR) 42.1 ms, flip angle (FA) 56°, reconstructed voxel size 1.82 × 1.82 × 8 mm, field of view (FOV) 349 × 349, matrix 192 × 192, pixel bandwidth 930 Hz, phase resolution sampling 70%, phase FOV 100%, and GeneRalized Autocalibrating Partial Parallel Acquisition (GRAPPA) acceleration factor 2.Modified Look-Locker inversion recovery (MOLLI) was implemented in a single breath hold at late diastole, using vendor-provided motion correction for T1 mapping based on image registration with synthetic image estimation . The 5 and two non-cardiac experts (a radiology technician with 15 years of experience and a non-cardiac radiologist with less than 1 year of experience in cardiac imaging) manually drew LV endocardial and epicardial contours once on the T1 map while carefully avoiding LV blood pool and epicardial fat  at three short-axis locations  using pixel-wise fitting of a three-parameter model :1\documeThe volumetric cardiac MR parameters were evaluated by a cardiac imaging post-processing radiology technician using QMASS software  and checked by a cardiac radiologist Table .Table 1Ct test or the Mann-Whitney U test as appropriate. On normal and abnormal heart function patient groups, each segment T1 quantification was reported both using mean ± standard deviation (SD) and median ± median absolute deviation (MAD) [Statistical normality testing of data distribution was assessed using the Shapiro-Wilk test using custom-written software (developed in MATLAB version 7.14) . Cardiacon (MAD) , 30 regat test for data evaluated by the mean and the Mann-Whitney U test for data evaluated by the median. Multiple comparisons across myocardial regions were done by the Kruskal-Wallis test with the Dunn-Bonferroni post hoc test adjustment. Statistical analyses were performed using IBM SPSS statistics software version 23 (IBM Corporation) with p < 0.05 considered as statistically significant.A coefficient of variance (CoV) of the T1 relaxation time was calculated as the SD of the difference divided by the mean and expressed in percentage. Comparison of T1 values between two patient groups on different LV regions was conducted using the independent sample p > 0.05). Their characteristics are listed in Table According to the criteria of Kawel-Boehm et al , 26 of 5The assessment of AHA 16 segments of LV myocardium from 26 normal patients and 31 abnormal heart function patients resulted in a total of 416 and 496 segments, respectively. With four observers assessing these segments, we obtained 1664 and 1984 segments, respectively.p = 0.532) and in abnormal heart function group (p = 0.628). This indicates that in statistically normally distributed data, median quantification is equivalent to the use of the mean. For segments with non-normally distributed pixel-wise T1 (subject for median quantification), a significant difference was found between the two T1 quantifications in both normal (p < 0.001) and abnormal heart (p = 0.003) function groups. This finding indicates that mean quantification cannot be used for statistical non-normally distributed data.In all segments of normal patients, statistical normality testing of pixel-wise native T1 per segment showed that 964 of 1664 segments (58%) were statistically non-normally distributed, whereas in all segments of abnormal patients, this statistical distribution was found in 1140 of 1984 segments (57%). In segments having statistically normally distributed pixel-wise T1 (subject for mean quantification), segmental T1 quantification by either mean or median showed no significant difference of T1 value in normal heart function group  Fig.  comparedIn a regional myocardial analysis Table , improvep = 0.059–0.879). When comparing the two patient groups using median quantification (Table p < 0.001–0.024) with exception in the mid-ventricular anteroseptal (p = 0.110) and basal anterior segments (p = 0.080). Heart function differentiation between the two patient groups is thus concluded to be significant in 14 myocardial segments (p < 0.001–0.040) by median quantification compared with only six (p < 0.001–0.042) when using the mean.Regional T1 analysis of four observers on different LV myocardial regions by using mean and median T1 quantification is presented in Tables on Table , signifip < 0.001–p = 0.023). However, in abnormal heart function patient group .Using median quantification, regional LV T1 value in normal heart function patient group was found to be significantly different in the three short-axis slices and in the three coronary artery territories attributed to the 16 AHA segments Fig.  , different short-axis slices, and different AHA segments elaborate on those in smaller studies of healthy subjects , 19. TheSuggested elsewhere –36, hearLimitations of this study are that it is retrospective and that patient separation into those having a normal heart function and those without a normal heart function was based on the cardiac MR functional parameters defined by thresholds of just one reported study , being, Some studies reported the association between diabetes mellitus and the progression of CMD , 44, 45.In conclusion, T1 assessment by observations of medians showed higher interobserver reproducibility compared with mean T1, regardless of statistical normality of data. Increased robustness of myocardial native T1 assessed by pixel-wise medians thus facilitates the early detection of heart function impairment and of differences between LV segments and between the different coronary artery territories.ESM 1(DOCX 56.9 kb)