The iShim sequence was used for IVIM data acquisition, and the diffusion parameters, D, D* and f values for IVIM, and conventional apparent diffusion coefficient (ADC) were evaluated on the anterior, posterior and lateral walls of the ventricular septum using the short axis of the heart. Significant differences were found in the D, D* and f values between healthy subjects and patients with old myocardial infarction and myocardial fibrosis (P = 0.000), with the median value of the D and f significantly smaller in the myocardial infarction and fibrosis than in the normal control but the median value of D* significantly greater in the myocardial infarction and fibrosis than in the normal control. In the receiver operating curve analysis, the areas under the curve were 0.939, 0.988 and 0.959 for the D, D* and f values, respectively. The sensitivities and specificities were 84.6% and 94.4% for D, 88.9% and 84.6% for D* and 100% and 93.1% for the f values, respectively. In conclusion, the IVIM-derived parameters  obtained using the iShim DWI technique showed high capacity in diagnosing old myocardial infarction and myocardial fibrosis by providing diffusion and perfusion information, which may have great importance in future clinical practice.Currently, little is known regarding the value of quantitative parameters derived from the intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) with integrated slice-specific shimming (iShim) sequence in detecting old myocardial infarction and myocardial fibrosis. This study was to investigate the value of IVIM-MRI with iShim sequence in diagnosing old myocardial infarction and fibrosis. Thirty-five patients with both old myocardial infarction and myocardial fibrosis and 12 healthy volunteers were prospectively enrolled to undergo cardiac diffusion-weighted imaging (DWI) using seven b-values (0, 20, 60, 80, 120, 200 and 600 s/mm However, a considerable number of patients cannot undergo enhanced cardiac scanning because of contrast agent allergy, renal fibrosis or other reasons.Myocardial infarction is one of the leading causes of death and disability worldwide, and its incidence in China is increasing annually. Myocardial fibrosis at the sites of old myocardial infarction is a determining factor of ventricular remodelling, which changes the mechanical and electrical activities of the heart and eventually leads to heart failure and death in severe cases. Thus, detection of myocardial fibrosis plays an important role in clinical treatment strategies. In recent decades, late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) has become the gold standard for evaluating myocardial infarction and localised fibrosisDiffusion-weighted imaging (DWI) is a quantitative detection method that can detect the diffusion of water molecules in the tissues; it is an imaging technique widely applied in many whole-body systems in clinical practice. However, the apparent diffusion coefficient (ADC) in traditional DWI is calculated using a single-exponential model based on the premise that the diffusion motion of water molecules in tissues follows a single Gaussian distribution, ignoring the effect of perfusion on the expansion motion. Moreover, myocardial ischaemic injury is generally caused by changes in myocardial perfusion. Thus, accurate assessment of myocardial diffusion and perfusion abnormalities is valuable in the diagnosis of cardiac ischaemic diseases.et al.3, enables evaluation of living tissue diffusion movement and micro-vessel perfusion in vivo using quantitative parameters obtained from the multi-b-value DWI of a double-exponential decay model. At present, the proposed theory has been widely used in studies of the head and neck4, liver5 and vertebral body6, with a relatively high diagnostic value. IVIM can reflect the diffusion and perfusion of living tissues through multi-parameter measurements. Therefore, IVIM may play an important supplementary role to conventional CMR in patients with heart disease who cannot tolerate drug therapy8. We hypothesized that the IVIM-DWI had a good value in diagnosing old myocardial infarction and myocardial fibrosis. This study consequently was performed to investigate the value of the diffusion coefficient , perfusion coefficient  and perfusion fraction  measured by the IVIM-DWI in diagnosing old myocardial infarction and myocardial fibrosis in comparison with healthy volunteers.The intravoxel incoherent motion (IVIM) theory, proposed by Le Bihan Thirty-five patients with both old myocardial infarction and fibrosis were prospectively enrolled between May 2016 and September 2018, comprising 28 males and 7 females aged 36–75 years with a mean age of 53.6 years. Another 12 healthy volunteers were also prospectively enrolled as the controls, comprising seven males and five females aged 23–53 years with a mean age of 35.7 years. The inclusion criteria were as follows: ① for patients, a definite medical history of myocardial infarction with duration of infarction ≥6 months; ② for healthy volunteers, no previous history of cardiopulmonary or cerebrovascular diseases and ③ for all subjects, multi-b-value DWI and contrast-enhanced magnetic resonance imaging (CE-MRI) were performed. The exclusion criteria were as follows: ① patients with severe arrhythmia or those failing to cooperate with the study and ② patients who could not undergo MRI examination . This study was approved by the Institutional Review Board of Handan Central Hospital, and written informed consent was obtained from all subjects including the healthy volunteers. All methods were performed in accordance with the relevant guidelines and regulations.2. The scanning parameters were as follows: frequency-coded field-of-view of 306 mm, phase-coded field-of-view of 75%, repetition time of 2,200.0 ms, echo time of 67 ms, layer thickness of 8 mm, scanning interval of 1.5–3.5 mm, number of excitation as 8.00 times, with local shimming, respiration navigator and ECG triggering technique integrated during the acquisition. Regarding directions of diffusion gradients, a three-scan trace diffusion gradient scheme was applied. In this scheme, the directions of diffusion gradient are orthogonal and line up with the directions of x, y and z axis.Imaging was performed with a 3.0-T MRI scanner  with a phased array surface coil. Respiration navigator and electrocardiogram (ECG) triggering technique were used in the course of the scanning. The planes included in the cardiac morphology examination included the routine two-chamber plane, four-chamber plane and a series of short-axis cine. Myocardial perfusion and delayed myocardial enhancement were performed in all the subjects. The IVIM-DWI was performed on the short axis of the heart with b-values of 0, 20, 60, 100, 150, 200 and 600 s/mm2/ms, b > 100 s/mm2) and the influence of the pseudo-diffusion term on the signal decay is quite small. Thus, in this higher b-value regime, the bi-exponential model can be simplified into an exponential fit equation:The LGE-positive segments of old myocardial infarction were analysed by two radiologists with 6 and 10 years of experience, respectively, in cardiovascular imaging diagnosis. The IVIM parameter maps were reconstructed using a prototype software . In this experiment, a more numerically-stable ‘segmented’ analysis procedure was performed, which is commonly used by most researchers to calculate the relevant parameters. In this method, because the value of D* is significantly greater than that of D, the b-value is significantly greater than ~1/D* (e.g. for D* ~10 µm2), whose zero intercept Sint is used along with the unweighted (b = 0) signal S0 to determine the f value, according to the following formula:Operationally, D value is determined from such a mono-exponential fit to data above a chosen threshold  to avoid overfitting the mono-exponential voxels. Subsequently, the parameter maps obtained for IVIM were transferred into a Syngo via workstation for measurement. To locate the infarcted myocardium with enhanced accuracy, short-axis delayed-enhancement positive images were selected in the delineated region of interest of the infarcted myocardium. Meanwhile, normal myocardium was evaluated at the anterior, posterior and lateral walls of the ventricular septum. Eventually, the D, D* and f values were obtained, and all the parameter values were expressed as mean ± standard deviation.Thus, finally, D* was calculated from the measured D and f values of the myocardium, in the old myocardial infarction of the patients and the normal myocardium of the healthy volunteers. Furthermore, the diagnostic value for the fibrosis of myocardial infarction was evaluated by receiver operating characteristic (ROC) curve analysis for the D, D* and f values, followed by the calculation of accuracy, sensitivity, specificity and the positive and negative predictive values in diagnosing the fibrosis of myocardial infarction. A P < 0.05 was considered to be statistically significant.The SPSS19.0 statistical software  was used for the analysis of the experimental data. Measurement data were expressed as mean ± SD (standard deviation). The rank sum test was performed for the D, D* and 2, the cardiac blood flow signal showed a high intensity and slightly raised signals in the myocardium. With increasing b-values, the cardiac blood flow signal decreased gradually to no signal, and the myocardium signal decreased gradually; the signal intensity of the myocardium was relatively low when the b-value was 600 s/mm2. Among the 35 patients with old myocardial infarction, 96 LGE-positive segments were found among 560 segments scanned in these 35 patients (16 segments for each patient). With the increase in the b-value, there was an increased trend in the signals of infarcted myocardium and a decreased trend in those of the surrounding normal tissues, resulting in a significant contrast . Furthermore, the area under the curves (AUC) in ROC analysis of the D, D* and f values in the two groups were 0.939, 0.988 and 0.959, respectively , by acquiring DWI images at several b-values (>4). Thus, such a model can be used to evaluate tissue diffusion and microcirculation perfusion simultaneously, indicating the great potential of this technique to accurately evaluate the myocardial perfusion and water molecular diffusion8. Additionally, the IVIM-DWI can provide micro-perfusion information, while avoiding the risks of contrast agent allergy and gadolinium-related renal fibrosis, as it avoids the need to inject the contrast agents.In the calculation of apparent diffusion coefficient (ADC) value, a least square method is used to fit the value because there is a linear relationship between b values and the logarithmically converted signal intensity. An equation of mean square difference (MSE) can be calculated using all the acquired b values. After the equation is established, the first derivative MSE equation is calculated, and then, the b value that can help getting the minimal MSE is calculated. For the calculation of D, D* and f values, a similar method was used according to a dual-exponential algorithm. As in other IVIM studies, a more numerically stable “segmented” analysis procedure was performed. Because D* is significantly greater than D, when the b-value is significantly greater than 1/D*, the influence of the pseudo-diffusion term on the signal decay is quite small. Thus, in this higher b-value regime, the algorithm can be simplified into a mono-exponential equation, whereby D and f can be estimated. With D and f values calculated previously, D *values can be calculated by using a partially constrained nonlinear fit of the entire dataset according to the dual-exponential algorithm. The DWI is an important examination method in functional MRI at present. However, the ADC value, calculated using the traditional single-exponential model, fails to consider the signal loss resulting from water molecular displacement caused by the intra-tissue microcirculation perfusion, thereby affecting the accuracy of tissue ADC value evaluation. Notably, the IVIM double-exponential model can calculate the D value (tissue diffusion movement), D* value (change of diffusion coefficient caused by microcirculation perfusion) and 7. In comparison with the conventional single-shot EPI sequencing, the advantages of the iShim sequencing lie in the facts that: (1) corresponding b-values can be selected reasonably according to the requirements of the experiment, especially when the b-values are small, so as to improve the fitting accuracy of the D* value8; (2) it can reduce image distortion; the iShim sequence scans a B0-Map before scanning each slice, and the signal changes of the B0-Map are used to correct the distortion of EPI, thereby contributing to the improvement in the distortion caused by the heterogeneity of the main magnetic field; (3) it can exert a better fat-suppression effect; specifically, the sequence can achieve a more thorough suppression of fatty tissue signals, by improving the accuracy of fat-selective pulses and using a slice-selection gradient-reversal fat-suppression technique; (4) it optimises the image acquisition mode, allows higher acquisition times, increases the signal-to-noise ratio and further improves the accuracy of parameter fitting. The setting of the b-value is also quite important in improving the accuracy of the parameter values. A lower b-value is more sensitive to perfusion of microcirculation, which, however, is prone to producing a ‘T2 penetration’ effect. Higher b-values may express a higher sensitivity to the diffusion of water molecules, but are also accompanied by a higher risk of image anatomical deformation and distortion that may affect the accuracy of the measurement11. In addition, in view of the continuous beating of the heart and the respiratory movement of the chest, breathing navigation technology and ECG-gated technology also play critical roles in improving the image quality. In this study, six low b-values, ranging 0–200 s/mm2, and one high b-value of 600 s/mm2 was selected for short axis DWI, in combination with the application of reduced field-of-view and local shimming. Meanwhile, respiratory navigation and ECG gating techniques were also used to improve the quality of the scanned images. Consequently, images of 35 patients with old myocardial infarction and 12 healthy volunteers were screened and included for analysis, without significant loss of myocardial signal and a clear display of myocardial contour.The infarcted myocardium of anterior and inferior segments was displayed as high signal on DWI Fig. . In ordeet al.12 confirmed the feasibility of IVIM imaging for the first time by using IVIM technology in the canine heart. Delattre et al.13 used an IVIM model of in vivo cardiac MRI and measured the parameters of IVIM in the human heart for the first time. In addition, Rapacchi et al.14 measured IVIM imaging of 10 normal human hearts by the EPI technology. In view of the results of these studies, all the experiments indicated that the D, D* and f values of 17-segment MRI of the left ventricle were not completely equal, despite the existence of some differences in the parameters, similar to the results of the present study. In our study, normal myocardial parameters were obtained in 12 healthy volunteers. D values of the anterior and inferior left ventricular septum were larger than those of the free wall myocardium, while converse results were found for the D* and f values, indicating significant differences among the parameters. The results suggested differences in the myocardial perfusion blood flow of the anterior descending branch, the right coronary artery and the circumflex branch. The 17-segment model is currently widely applied worldwide for left ventricle segmentation15. Different segments of the left ventricle are supplied by the anterior descending branch, the circumflex branch and the right coronary artery. Because most of the Chinese population have the right dominant type of coronary artery, the anterior wall and anterior ventricular septum of the left ventricle are thus mainly supplied by the anterior descending branch, the inferior wall and inferior septum are mostly supplied by the right coronary artery, and the lateral wall is predominantly supplied by the circumflex branch. The blood flow of the anterior descending branch and the right coronary artery is generally larger than that of the left circumflex artery. Thus, the results of this experiment were reasonable to certain extent. Power analysis showed that the total sample size in our study is enough to draw the conclusion with well over 80% power. In a study conducted by Kociemba et al.16, a 1.5 T MR scanner was used, and DWI sequences with b-values of 0, 50, 100 and 200 s/mm2 were used for cardiac scanning. The results showed that the DWI possessed high sensitivity and specificity in the detection of acute myocardial infarction. Furthermore, in a study by Laissy et al.17, the ADC value in the healthy volunteers was higher than in patients with myocardial infarction in different periods, when the b-value of a 1.5 T MR scanner was approximately 300 s/mm2, consistent with the results demonstrated in our study. Our study indicated that the D and f values of infarcted myocardium in 35 patients with old myocardial infarction were significantly lower than those in the 12 healthy volunteers and that the D* value was significantly higher than that of the normal myocardium. We speculated that this was related to decreased blood perfusion caused by ischaemic necrosis and infarcted myocardium with decreased blood flow. Moreover, the AUCs of the D, D* and f values were 0.939, 0.988 and 0.959, respectively, with no significant difference in the diagnostic efficiency. Furthermore, the infarcted myocardium of 35 patients with old myocardial infarction showed high signal on DWI in a bi-exponential model. When b = 0 s/mm2, the signal intensity of the blood pool was high, which easily affected the display of the subendocardial infarcted myocardium22. With an increasing b-value, the intracardiac blood pool showed low signals, and thus, a higher b-value might induce a more obvious contrast between infarcted and normal myocardium, aiding the diagnosis of infarcted myocardium.In 2003, Callot 26. At present, delayed enhancement is the gold standard for the diagnosis of fibrosis in old myocardial infarction, which, however, possesses deficiencies due to the requirement for injection of contrast agent, long scanning time and no quantitative indicators. However, the IVIM-DWI technology can display and quantitatively detect myocardial fibrous scars without the need for gadolinium-containing contrast agents, with corresponding precision, confirmed experimentally29. The mechanism leading to decreased D and f values but increased D* value in the fibrosis of myocardium in IVIM of MRI may include the following several aspects. As increase of the fibrous connective tissue component in the fibrous myocardium, especially increase of the collagen fiber composition, the Brownian motion of water molecules of the fibrous myocardium is damaged, resulting in decrease of the D and f values. Fibrosis of the myocardium is accompanied by degeneration of myocardial cells to cause increase of the tissue space of the myocardial collagen fibers, leading to decreased perfusion and subsequent increase of the D* value. In our study using the IVIM dual-exponential algorithm for imaging the myocardium with several b values, the D, D* and f values can be simultaneously obtained to reflect the water movement, dispersion and blood microcirculation perfusion state. As increase of the b values, the myocardial signal begins to attenuate, and the infarcted myocardium is of high signal. The D, D* and f values measured quantitatively with the LGE standard in the normal and infarcted myocardium were analyzed to determine the cut-off value, sensitivity, specificity and AUC, which demonstrated high values of these parameters in diagnosis of myocardial infarction. The results of the current study also supported the hypothesis that IVIM-DWI can diagnose old myocardial infarction more easily, and the parameters of the D, D* and f values can quantitatively evaluate the extent and degree of myocardial infarction fibrosis. Therefore, the IVIM-DWI has a certain value in demonstrating the blood perfusion and water molecular diffusion of old myocardial infarction.Quantitative detection of fibrosis in old myocardial infarction plays an important role in evaluating the degree of left ventricular dysfunction and progression to heart failureThis study has some limitations including a limited cohort, retrospective nature, non-randomization, single center study and only Chinese ethnicity involved. Future studies will have to solve the problems for better outcomes.f) obtained using the iShim DWI technique showed high capacity in diagnosing old myocardial infarction and myocardial fibrosis by providing diffusion and perfusion information, which may have great importance in future clinical practice.In conclusion, the IVIM-derived parameters (D, D* and


T-wave alternans (TWA), a marker of electrical instability, can be modulated by cardiac resynchronization therapy (CRT). The relationship between TWA and heart failure response to CRT has not been clearly defined.alt >0μV, k≥3), its duration (d), and burden  were quantified in moving 128-beat segments during incremental atrial  and atrio-biventricular (DDD-CRT) pacing. The immediate and long-term effect of CRT on TWA was examined. Clinical response to CRT was defined as an increase in LVEF of ≥5%. Native-TWA was clinically significant  in 68% of subjects at baseline. Compared to native-TWA at baseline, DDD-CRT pacing at baseline and follow-up reduced the number of positive TWA segments, peak-magnitude, longest-duration and peak-burden of TWA . In addition, the number of positive segments and longest-duration of native-TWA diminished during follow-up . Clinical response to CRT was observed in 71% of patients; the reduction in DDD-CRT paced TWA both at baseline and follow-up was present only in responders .In 40-patients , TWA was evaluated prospectively at median of 2 months (baseline) and 8 months (follow-up) post-CRT implant. TWA-magnitude (VLong-term CRT reduces the prevalence and magnitude of TWA. This CRT induced beneficial electrical remodeling is a marker of clinical response after CRT. Mechanical coordination of left ventricle (LV) with long-term cardiac resynchronization therapy (CRT) has been shown to reverse LV structural and molecular remodeling in cardiomyopathy patients with wide left bundle branch block (LBBB) and LV dysfunction. In particular, sarcomeric proteins, sarcoplasmic reticulum calcium ATPase 2α (SERCA) and ryanodine receptor (RyR) levels are restored, resulting in augmentation of excitation-contraction coupling and intracellular calcium cycling ,2. In adThe effect of CRT on cardiac repolarization heterogeneity, a ventricular arrhythmia (VA) risk marker remains under studied. There are no longitudinal data that have tracked changes in ventricular repolarization with clinical response after long-term CRT. Microvolt T-wave alternans (TWA) arises from abnormal intracellular calcium cycling, due in part to reduced SERCA in cardiomyopathy, and is an indicator of ventricular repolarization instability . AccordiForty patients with ischemic or non-ischemic dilated cardiomyopathy undergoing CRT with defibrillator (CRT-D) implantation as per heart-failure management and sudden cardiac death prevention guidelines were prospectively enrolled. All patients had a baseline echocardiographic LV ejection fraction (EF) ≤ 35%, native QRS duration >130ms, New York Heart Association (NYHA) functional class ≥ 2 and had received guideline recommended optimal medical therapy for at least 3-months prior to consideration of CRT. Patients with heart-failure undergoing an upgrade of implantable cardioverter defibrillator (ICD) to CRT-D or those with a history of spontaneous VA were also included. Patients with an AV-block indication for pacing, recent acute coronary event in the last 1-month, and decompensated heart-failure were excluded.All patients underwent transvenous implantation of an atrial lead in the right atrium, high voltage right ventricular (RV) lead in the RV apex, and LV lead in a postero-lateral or lateral tributary of the coronary sinus. Septal and apical LV stimulation were avoided when feasible. The CRT therapy began immediately after the implant. Permanent CRT programming of AV and VV delays and LV stimulation vector was optimized individually for each patient as per the discretion of treating electrophysiologist based on the intrinsic PR interval and paced QRS morphology. In addition, VA detection and therapy programming were all standardized depending on the primary or secondary prevention ICD indication. All patients provided written informed consent and the study was approved by the research ethics board at University Health Network, Toronto.The TWA measurements were made within the first 3 months after CRT therapy initiation (baseline) and then at least 6 months after the initial study (follow-up). The peri-implant period (until 1 month after implant) was avoided for the baseline study to minimize any spurious results from changing autonomic tone arising from volume shifts, fasting, analgesia, incisional pain, or stress related to the procedure. After careful skin preparation, standard 12-lead ECG electrodes were applied and continuous ECG was recorded in the recumbent position using a digital 12-lead Holter monitor  at 1024Hz sample rate . Atrial (AAI) pacing serially at 100, 110 and 120 bpm for 3-minute duration at each rate, followed by atrio-biventricular (DDD-CRT) pacing in similar rate sequence, was performed through non-invasive wireless telemetry. A recovery period of 5-minutes of DDD-CRT pacing at the intrinsic heart rate was set in-between the AAI and DDD-CRT pacing sequels to minimize any confounding effects from rapid pacing induced APD alternans hysteresis ) and categorical variables were expressed as counts or percentages. To account for repeated measurements at 3 different pacing rates for each pacing type (AAI or DDD-CRT), changes in TWA measurements between the pacing types  (baseline TWA study) and 8 months (IQR 7 to 12) (follow-up TWA study) post-CRT implant. Of the 8 patients on amiodarone at baseline, 2 were taken off and 1 additional patient started amiodarone before the follow-up study. Six patients underwent clinically indicated reprogramming of AV/VV delays and 1 patient was programmed to VVT mode due to persistent atrial fibrillation between the baseline and follow-up study. No patient required repositioning of LV lead. Patients received an average of 94±14% and 96±14% biventricular pacing before the baseline and follow-up study respectively.The QRS duration reduced from 166±31ms (unpaced) to 152±36ms (CRT paced) at the time of implant (p = 0.003), with 24 (60%) patients achieving a dominant R-wave in lead V1 and S-wave in leads I and V6. The native QRS duration at follow-up was 164±21 ms, which was similar to the baseline unpaced QRS duration (p = 0.2).Of the 40 patients, AAI pacing could not be performed in 13 patients (32%) at the baseline study due to atrial fibrillation (n = 3) or AV block during atrial pacing ≥ 100/min (n = 10). In the remaining patients, who satisfactorily completed at least one AAI pacing protocol, native TWA was clinically significant in 65% of subjects. In these patients, TWA was present in 70±7% of recorded 128-beat segments with a peak magnitude of 8±1 μV, longest duration of 143±7 seconds and peak burden of 400±97 μV.sec.Compared to native TWA at the baseline study, initiation of DDD-CRT instantly reduced the number of positive TWA segments by 10±4% (p = 0.02), peak TWA magnitude by 1.8±0.7 μV (p = 0.01), longest TWA duration by 20±7 seconds (p = 0.004) and peak TWA burden by 156± 60 μV.second (p = 0.01) . When coOf the 40 patients, 12 patients (30%) could not complete AAI pacing at the follow-up study due to atrial fibrillation (n = 3), pacing induced atrial flutter (n = 1) or AV block during atrial pacing ≥ 100/min (n = 8). Of the 10 patients who had AV block at their baseline study, 6 patients exhibited AV block during follow-up study as well. In addition, 2 patients showed AV block for the first time at their follow-up study. The prevalence of clinically significant native TWA decreased from 65% at baseline to 52% at follow-up, but this difference did not reach statistical significance (p = 0.09). Additionally, compared to native TWA at baseline, the number of positive segments and longest-duration of native TWA diminished by 8±4% (p = 0.044) and 17±7sec (p = 0.02), respectively, during follow-up, with primary reduction observed at 100 and 110 bpm but not at 120bpm . The peak magnitude and peak burden of native TWA, however, remained unchanged (p = 0.4 and 0.6 respectively), at all pacing rates (interaction p = 0.4 and 0.2 respectively).Progressive and greater reduction in all TWA measures was observed during DDD-CRT pacing at follow-up. Compared to native TWA at baseline, the number of positive TWA segments reduced by 14±4% (p = 0.002), peak TWA magnitude by 1.9±0.8 μV (p = 0.01), longest TWA duration by 27±8 seconds (p<0.001) and peak TWA burden by 176± 61 μV.second (p = 0.004) during DDD-CRT pacing . In addiMoreover, there was a trend towards reduction in the number of positive TWA segments between baseline and follow-up DDD-CRT pacing (p = 0.096). Notably, a significant reduction in various TWA measures was observed between baseline and follow-up DDD-CRT pacing at a higher pacing rate of 120 bpm . A representative case example of the TWA measures at baseline and follow-up with AAI and DDD-CRT pacing is shown in Echocardiographic reassessment of LVEF was done in 38 of 40 (95%) patients at median 10 months (IQR 7 to 15) after CRT implant. In these patients, LVEF improved from 24±7% pre-implant to 34±10% (p<0.0001) at follow up. The LVEF recovered by ≥5% leading to a final LVEF of ≥20% in 27 of 38 (71%) patients who were regarded as CRT responders. Two patients who had medical assessments without echocardiogram were excluded from CRT response analysis.There was no difference in the native QRS duration, LBBB prevalence and other baseline characteristics between responders and nonresponders to CRT  . HoweverAfter a median follow-up of 15 months (IQR 8 to 25), 3 (7.5%) patients received appropriate ICD therapy for VA, and 1 patient died of cancer. Patients with and without VA events had similar reduction in TWA at baseline and long-term CRT .Our study demonstrated that immediate and long-term electric resynchronization with CRT reduces microvolt TWA in cardiomyopathy patients with intrinsic conduction disease and heart-failure. The main findings of the study are: 1) Initiation of CRT immediately reduces the prevalence and magnitude of TWA. 2) Progressive reduction in prevalence and magnitude of DDD-CRT paced TWA is observed after long-term CRT. 3) Long-term CRT also reduces the prevalence of native TWA but its magnitude does not change. 4) Reduction in DDD-CRT paced TWA is strongly related to clinical response to CRT.Electrical resynchronization of the ventricles with CRT is mediated by fusion of RV and LV propagating wavefronts. As a result, any pre-existing lines of functional conduction block disappear which reduces global activation time mainly in the LV epicardium . Notablypeak-Tend intervals [CRT however, does not alleviate prolonged endocardial conduction time in the LV, and epicardial to endocardial dysynchronous activation may persist that can enhance transmural dispersion in tissue refractoriness . Initiatntervals . Despitentervals . In expentervals . With acImmediate reduction in DDD-CRT paced TWA was seen specifically in patients who eventually had clinical response to CRT. A potential reason could be the preferential contribution of ventricular ion-current remodeling versus myocardial scarring to the cardiomyopathic substrate in these patients. Although we did not evaluate presence and amount of myocardial scar, it is conceivable that conduction delay in patients who exhibited immediate reduction in TWA was primarily due to ventricular electrical conduction remodeling that later responded clinically to CRT as well, thereby permitting immediate TWA reduction to predict mechanical LV function improvement. In contrast, failure to achieve immediate TWA reduction was possibly due to greater ventricular scar burden that may have also generated non-response to CRT and worse LVEF outcomes ,17.Long-term CRT attempts to normalize the pattern of LV activation that ultimately can promote several structural and molecular changes in the cardiac electric substrate (i.e. mechano-electric feedback). Besides At the 6-months follow-up study, we observed further reduction in the magnitude and prevalence of DDD-CRT paced TWA compared to the baseline native TWA. Moreover, the prevalence of native TWA also decreased significantly. These late changes in TWA predominated in CRT responders, while nonresponders not only failed to achieve equivalent reduction but also had worsening in both DDD-CRT paced and native TWA. There are several potential mechanisms that may explain these findings. Foremost, long-term CRT pacing in clinical studies up regulates SERCA, RyR, and sodium-calcium exchanger, which can improve intracellular calcium cycling and reduce cytosolic calcium alternans. Cytosolic calcium in turn can modulate APD via L-type calcium currents and the sodium-calcium exchanger. In experimental preparations, a reduction in cytosolic calcium alternans has been shown to reduce repolarization alternans. ,2,16In addition, long-term CRT pacing can remodel several sarcolemmal ion channels, resulting in APD shortening and flatten of the APD restitution relationship . In expeAnother plausible mechanism for long-term CRT induced-TWA remodeling involves weakening of LBBB related long-term cardiac memory, which can also modulate repolarization alternans. In heart failure patients with LBBB, the abnormal vector of activation can create large spatial dispersions in APD between early and late-activated segments. By altering the direction of activation with long-term CRT, these spatial APD gradients can also resolve as is evident by a change in T wave amplitude and morphology ,18,20,21alt during biventricular pacing that identifies a patient population at high risk of clinical events [Ehrlich et al showed 83% concordance between microvolt TWA test results obtained during right atrial and DDD-CRT pacing at the time of CRT implant . Howeverl events . In theiRecently, Hua et al reported 30% reduction in the prevalence of alternans in local epicardial LV electrogram-T wave during AAI pacing after 3 months of CRT . PatientWe demonstrated that CRT pacing reduced TWA impressively in cardiomyopathy patients, primarily in those who had mechanical LV function improvement with CRT. Importantly, reduction in TWA in CRT responders was observed immediately at the baseline study well before LVEF recovery may have occurred. This beneficial TWA response was sustained and progressive as confirmed at the follow-up TWA study. Such reductions in TWA were seen despite minimal reduction in CRT-paced and native QRS duration. Immediate and long-term change in TWA particularly with DDD-CRT pacing can therefore be an important prognostic marker for mechanical recovery after CRT.Treatment of LV conduction delay with CRT does not counter long trans-septal conduction time, and LV endocardial dysynchrony may persist . MoreoveThe small sample size is a limitation, however significant differences between baseline and follow-up TWA study were demonstrable. Fewer VA events in our cardiomyopathy cohort precluded any meaningful analysis of clinical benefit of long-term CRT-induced TWA remodeling on VA burden. Second, baseline study performed at a median 2 months after CRT initiation may not have captured true baseline TWA as some patients may already have had substantial electrical and mechanical remodelling within weeks of CRT ,26–29. HLong-term CRT reduces the prevalence of native TWA without changing native QRS duration. Sustained reduction in the prevalence and magnitude of DDD-CRT paced TWA is also observed. These findings provide evidence for long-term CRT induced repolarization remodeling in patients with cardiomyopathy. The effect is closely dependent on CRT response and is a marker of mechanical recovery of LV with CRT.S1 File(DOCX)Click here for additional data file.


There are still many pendent issues about the effective evaluation of cardiac resynchronization therapy impact on functional mitral regurgitation. In order to reduce the intrinsic difficulties of quantification of functional mitral regurgitation itself, an automatic quantification of real-time three-dimensional full-volume color Doppler transthoracic echocardiography was proposed as a new, rapid, and accurate method for the assessment of functional mitral regurgitation severity. Recent studies suggested that images of left ventricle flow by echo-particle imaging velocimetry could be a useful marker of synchrony. Echo-particle imaging velocimetry has shown that regional anomalies of synchrony/synergy of the left ventricle are related to the alteration, reduction, or suppression of the physiological intracavitary pressure gradients.We describe a case in which the two technologies are used in combination during acute echocardiographic optimization of left pacing vector in a 63-year-old man, Caucasian, who showed worsening heart failure symptoms a few days after an implant, and the effect of the device’s optimization at 6-month follow-up.φ), can represent improvement of fluid dynamics synchrony of the left ventricle, and explain, with a new deterministic parameter, the effects of cardiac resynchronization therapy on functional mitral regurgitation. Real-time three-dimensional color flow Doppler quantification is feasible and accurate for measurement of mitral inflow, left ventricular outflow stroke volumes, and functional mitral regurgitation severity.The degree of realignment of hemodynamic forces, with quantitative analysis of the orientation of blood flow momentum  contains supplementary material, which is available to authorized users. The role of echocardiographic imaging is essential in the follow-up of patients after cardiac resynchronization therapy (CRT). Dysfunction of the device can be discovered by echo control with a multiparametric approach. This is the first case report in which automatic quantification of real-time three-dimensional full-volume color Doppler transthoracic echocardiography (FVCD) has been proposed as a new, rapid, and accurate method for the assessment of functional mitral regurgitation (FMR) severity pre-CRT and post-CRT, in combination with fluid dynamic approach using echo-particle imaging velocimetry (echo-PIV) technique.φ), which represents a new deterministic parameter of fluid dynamics synchrony. The combined approach can explain the effects of CRT on the realignment of hemodynamic forces involved in the pathophysiologic determinants of FMR. The short time of post-processing during acute study would increase the cultural interaction between electrophysiologist and echocardiographer, with lower costs required than those necessary for invasive monitoring of cardiac performance that can be used only during implantation of the device.Reduction in FMR is one of the mechanisms by which CRT exerts its beneficial effects. This innovative and combined approach can allow a more effective optimization of the biventricular device at follow-up. The quantification of mitral insufficiency during acute study can be associated with the quantitative analysis of the orientation of blood flow momentum  IV class, and left bundle branch block . He was referred for CRT-D upgrade, awaiting cardiac transplantation, despite optimal medical therapy: b-Blockade, loop-diuretic, angiotensin-converting enzyme (ACE) inhibitor, K-sparing agent, and ivabradine. Standard clinical imaging protocol revealed a dilated left ventricle with an end-systolic volume (ESV) of 380 ml, an ejection fraction (EF) of 4.8% as measured by the modified Simpson’s method, and severe FMR, assessed by qualitative estimation with two-dimensional color flow Doppler approach, showing a very large central jet and reaching the posterior wall of the left atrium He underwent the implant of a CRT-D device with a quadripolar left ventricular (LV) lead placed in the posterolateral branch of the coronary sinus. After recording the right ventricle (RV)-to-LV electrical delay at each of the four LV rings, we chose the A1 unipolar vector for LV pacing .At 13-day post-implant follow-up, he showed worsening heart failure (HF) symptoms and only A2 unipolar LV vector configuration, with interventricular (VV) interval of 0 ms, was suitable for simultaneous biventricular activation  as quantified by the large value of their mean angle φ . A first setting option  reducing the angle (φ = 45°), and increasing the delay  reducing the angle (φ = 40.3°). Eventually, the sequential biventricular activation with delay − 50 ms .Without pacing stimulation . (WMV 692 kb)Additional file 3:Video S3. Cardiac resynchronization therapy ON with interventricular delay 0 ms (Video 3). (WMV 4820 kb)Additional file 4:Videos S4. Cardiac resynchronization therapy ON with interventricular delay − 30 ms (Video 4). (WMV 247 kb)Additional file 5:Video S5. Cardiac resynchronization therapy ON with interventricular delay − 50 ms (Video 5). (WMV 645 kb)No reduction of FMR by three-dimensional FVCD, during the same acute study with shutdown versus reactivation of device, was demonstrated, as shown in Figure Additional file 6:Videos S6. Real-time three-dimensional color flow Doppler quantification at 13-day follow-up, during acute study: cardiac resynchronization therapy OFF (Video 6). (WMV 559 kb)Additional file 7:Video S7. Cardiac resynchronization therapy ON with interventricular delay 0 ms (Video 7). (WMV 559 kb)The data acquisition time, by three-chamber apical view, for each three-dimensional color Doppler data set was approximately 5 seconds, and it took less than 3 minutes to analyze the average regurgitation volume, with automated anatomy detection of the LV endocardial border, mitral annulus (MA), LV outflow (LVOT), and placement of three-dimensional hemispheric flow sampling planes in the MA and LVOT. The software of three-dimensional FVCD computed the flow volumes as the area under the curve of both the MA and LVOT flow in three cardiac cycles, and FMR volume was calculated by subtracting LVOT stroke volume from MA stroke volume.Our patient showed an improvement of NYHA class (III versus IV) and LV EF (26.6% versus 4.8%). Significant reduction of ESV (288 ml versus 380 ml) and persistent improvement of diastolic function were obtained. The regularized function is noticeable in Additional file 8: Video S8  and it is summarized in Fig. Additional file 8:Video S8. Transthoracic echocardiogram apical four-chamber view, at 6-month follow-up showing a dilated left ventricle post-implant, with moderate-to-severe functional mitral regurgitation, assessed by qualitative estimation with two-dimensional color flow Doppler approach, with a smaller central jet and no reaching of the posterior wall of the left atrium. (WMV 231 kb)Additional file 9:Video S9. Real-time three-dimensional color flow Doppler quantification at 6-month follow-up. (WMV 638 kb)φ = 43.1°.The intraventricular forces estimated by echo-PIV were still partially dominated by the longitudinal path of pressure gradient et al. have shown that the quantification of FMR before and after percutaneous MV repair by three-dimensional FVCD was comparable to the integrative visual assessment and more reliable than the PW Doppler method [et al. have described the accuracy and feasibility of computing mitral, aortic, tricuspid, and pulmonic stroke volumes using three-dimensional FVCD in children, to compute valve areas and regurgitant volumes [The availability of pacing configurations offered by quadripolar LV leads could improve patients’ response to CRT, in terms of reduction of FMR, by improving cardiac synchrony; however, the selection of an optimal setting remains a challenge, and the correct quantitative evaluation of FMR suffers from well-known pitfalls and systematic inaccuracy. The need for shape assumptions and the inability to account for the dynamic regurgitant orifices are technical limitations to two-dimensional proximal isovelocity surface area (PISA)-based effective regurgitant orifice area (EROA) and regurgitant volume measurements, especially in patients with FMR where the regurgitant orifice is thought to be largest at the beginning and end of systole, and smallest in the middle. Pulsed wave (PW) Doppler-based flow quantification techniques with two-dimensional transthoracic echocardiogram have been used to measure mitral inflow and aortic stroke volumes. This information is also used in computing flow-derived valve area in stenotic valve disease and regurgitant volume and fraction in valvular regurgitation. We know that the assumption of circular geometry of LVOT is erroneous and affects the calculation of aortic valve area by continuity equation, and the effect of spatially non-uniform flow on the continuity equation has not been clearly evaluated. Small errors in measurements of LVOT or mitral annular diameter are squared in the computation of stroke volume, and may lead to large differences of results during acute study. Moreover, PW Doppler of LVOT flow and MA flow are obtained in a separate echocardiographic windows, the timing of the measurements are different and can introduce error. Current three-dimensional color Doppler-based methods require the operator to trace the area of color flow and use electrocardiographically gated three-dimensional echo over an acquisition of more than seven complete cardiac cycles. Furthermore, as arrhythmias and respiratory movement generate a stitching artifact, it is necessary to optimize acquisition via sinus rhythm gating and breath holding. At the same time, a novel real-time three-dimensional FVCD, based on instantaneous acquisition of a single cardiac cycle, has been reported as an innovative method to assess FMR  without r method . Kato et volumes . These a volumes . Intraca volumes . This isφ) of the global hemodynamic forces exchanged between blood and surrounding tissues. Many echocardiographic studies have demonstrated how CRT can contrast all the pathophysiologic determinants of FMR by minimizing LV dyssynchrony due to the following: increasing “closing forces” , reducing “tethering forces” , reshaping annular geometry and function , and correcting diastolic mitral regurgitation (atrioventricular synchronization). The role for routine VV delay optimization post-CRT is not clear. Most studies have shown that a majority of patients have optimal VV intervals that are within a range of ±20 milliseconds. Simultaneous biventricular pacing or pre-excitation of LV most often remains a challenge. VV delay optimization is generally performed by changing the VV sequence, starting with the LV being activated before the RV, and then stepwise lengthening or shortening of the VV interval  and measuring the highest aortic time-velocity integral (Ao IVT), but this simplified echocardiographic approach is susceptible to inter-observer variability because there is a significant manual interaction with the data post-processing. Furthermore, the availability of pacing configurations offered by quadripolar left ventricle leads could improve a patient’s response; however, selection of an optimal setting remains a challenge. Recent studies suggested that images of LV flow by echo-PIV could be a useful marker of synchrony [φ), can represent improvement of fluid dynamics synchrony of the LV, and explain with a new deterministic parameter the effects of CRT on all the pathophysiologic determinants of FMR through the increase of “closing forces,” reduction of the “tethering forces,” a reshape of the annular geometry and function, and the correction of diastolic mitral regurgitation, respectively.Echo-PIV is an optical method where the contrast agent bubbles are tracked from one frame to the next to calculate the instantaneous blood velocity field. Echo-PIV has shown that regional anomalies of synchrony of the LV are related to the alteration of the physiological intracavitary pressure gradients that deviate from their natural longitudinal orientation , 8. Thisynchrony . The vorynchrony –12. LV fynchrony , and theynchrony , 8, 14. ynchrony . The appynchrony , 17, altThis clinical case offers an innovative and accurate approach for acute echocardiographic optimization of left pacing vector. It shows the clinical utility of combined three-dimensional FVCD/echo-PIV assessment to increase response to CRT, in terms of reduction of FMR, improving fluid dynamics synchrony of the LV.


Background and objectives: Chronic kidney disease (CKD) increases the risk of cardiovascular diseases even in its early stages and is associated with structural and functional cardiac abnormalities. The aim of this study was to use speckle-tracking echocardiography (STE) to evaluate left and right ventricle mechanics and function, markers of subclinical dysfunction in patients with end-stage renal disease (ESRD) undergoing haemodialysis. Methods: Patients with ESRD undergoing regular haemodialysis and with preserved left ventricle (LV) ejection fraction (EF) (n = 38) were enrolled in this retrospective study. The control group consisted of 32 age-matched persons with normal kidney function (glomerular filtration rate (GFR) >90 mL/min/1.73 m2 according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)). Conventional 2D echocardiography and STE were performed in all patients. Results: 70 individuals, 31 (44.29%) males and 39 (55.71%) females, were included in the study. There were no significant differences in age, sex and body surface area between the groups. LV end diastolic diameter did not differ between the groups, while LV myocardial mass index was higher in the group of patients on haemodialysis  and LV diastolic dysfunction (LVDD) was found in 31 (81.6%) patients of this group. LV global longitudinal strain (GLS)  and LV global circumferential strain (GCS) at the mitral valve and papillary muscles levels  were significantly lower in haemodialysis group patients. The parameters of the right ventricle (RV) free wall longitudinal function including RV GLS , were reduced in haemodialysis patients compared with the controls. However, RV fractional area change (FAC) did not differ between the groups (p = 0.19). Conclusion: Patients with ESRD and preserved LV ejection fraction undergoing haemodialysis had a higher prevalence of LVDD and impaired LV longitudinal and circumferential deformation indices, as well as reduced RV longitudinal function and deformation parameters compared with the age-matched healthy controls. STE helps to detect subclinical LV and RV dysfunction in chronic haemodialysis patients. The incidence of chronic kidney disease (CKD) is increasing globally, however, recent data have shown heterogeneity of CKD prevalence in the general population, varying from ∼5% to 13% across different countries . CardiovConventional echocardiography is not sensitive enough to detect early cardiac dysfunction in CKD patients . Novel 2Only few studies have used STE to measure myocardial deformation parameters to assess biventricular function in patients with ESRD ,15,16,172 according to CKD-EPI) [This was a retrospective study that included patients with ESRD undergoing chronic haemodialysis without known clinically significant cardiovascular pathology, without signs and symptoms of heart failure and with preserved LV EF on echocardiography. A total of 38 patients undergoing haemodialysis at the Department of Detoxication at the Hospital of the Lithuanian University of Health Sciences Kauno klinikos were enrolled in the study  between October 2016 and June 2017. All haemodialysis patients were maintained on regular haemodialysis (three sessions/week for 4 h/session). An arteriovenous fistula or a long-term internal jugular haemodialysis catheter were used as a vascular access. A blood flow rate of 300–400 mL/min, a dialysate flow rate of 500–700 mL/min and a synthetic hollow fibre dialysers were used. A total of 32 age-matched healthy persons with normal kidney function (GFR > 90 mL/min/1.73 mCKD-EPI)  were inv2D echocardiography was performed by an experienced cardiologist and echocardiogram data were gathered on a non-dialysis day to avoid the effect of HD-induced myocardial stunning on echocardiogram results. A conventional echocardiography system  with a 3.5 MHz transducer was used. The frame rate used for the analysis was 82–95 frames/s. A 12-lead electrocardiogram was taken throughout the test. Conventional measurements were obtained according to the recommendations of the American Association of Echocardiography . LV end-diastolic diameter (EDD) was evaluated from the parasternal long-axis view, while basal right ventricular diameter (RVD1) was assessed from the RV focused four-chamber view at the end-diastole. Left atrium (LA) diameter was measured from the parasternal long-axis view and right atrial (RA) diameter was measured from the apical four-chamber view at the end-systole. LA and RA maximal volumes were obtained by the area-length method . LV myocLV EF was calculated using Simpson’s biplane method with manual tracing of the endocardial borders at the end-diastole and the end-systole at the apical four- and two-chamber views. The function of the LV long axis was assessed using tissue Doppler imaging (TDI) by measuring the peak systolic velocity of mitral annulus as LV S′ of septal, lateral, inferior and anterior walls . LV diasRV longitudinal function was evaluated by measuring the tricuspid annular plane systolic excursion (TAPSE) using the M-mode, while the peak systolic velocity of tricuspid annulus (RV S′) was obtained by TDI and RV fractional area change (FAC) by tracing the RV endocardial borders at the end-diastole and the end-systole . Off-line speckle-tracking analysis  was performed using images obtained by the conventional echocardiography. Cardiac cycles associated with premature atrial or ventricular beats were excluded. The endocardial borders for strain measurements were traced automatically with the aid of manually-marked reference points at the end-systolic frame. Closure of the aortic valve was identified as a sign of the end-systole. If the quality of automatic tracking was poor, the reference points were manually readjusted until satisfactory tracking was achieved. After satisfactory tracking was obtained, graphical and numerical displays of myocardial deformation parameters were generated automatically. The estimated myocardial deformation parameters included LV and RV global longitudinal strain (GLS) and global longitudinal peak systolic strain (GLPSS), LV global circumferential strain (GCS), LV global circumferential peak systolic strain (GCPSS) and LV global radial strain (GRS). Peak radial and circumferential strains were measured from the LV short-axis views at the mitral valve, papillary muscle and apex levels. Peak longitudinal strain was measured from the apical four- and two-chamber views. Global strain analysis was evaluated according to the existing guidelines . GLS wasn = 1/(∆2 + 1/N), n—sample size, ∆—type I error (0.05), N—population size . Calculated sample size was 34 patients. Our statistical study power was calculated for both groups of patients for one of the main parameters of LV function (GLS) using a statistical test and resulted in an actual power of 0.99 in a total sample size of 70 with alpha level 0.05. Shapiro-Wilk test was used to determine the distribution of data in both haemodialysis and control groups. Differences in the characteristics of the groups were assessed using unpaired Student’s t-tests  and Mann-Whitney tests  for continuous variables. Chi-squared tests were used to compare categorical variables. p < 0.05 was considered to be statistically significant.Statistical analysis was performed using SPSS 20.0 software. Data are presented as mean (standard deviation (SD)) and as median (interquartile range (IQR)) for continuous variables and as frequencies (percentages) for categorical variables. Sample size was calculated using formula n = 32, 84.21%) with ESRD had a standard haemodialysis access by an arteriovenous fistula (AVF): 27 (71.05%) of them had a radial AVF and 5 (13.16%) had a brachial AVF. In the remaining 6 (15.79%) haemodialysis patients was performed using a permanent central venous catheter. 6 patients had had previous kidney transplantation. Most of the patients  had a dialysis vintage of >1 year. The incidence of AH and DM did not differ between the study groups. AH was highly expressed in the haemodialysis group and it was controlled with antihypertensive medications. 22 (57.9%) haemodialysis patients were on angiotensin-converting-enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) and 23 (60.5%)—on beta blockers. A total of 70 patients, 31 (44.29%) male and 39 (55.71%) female, were included in the study. There were no significant differences in age, sex and body surface area between the groups. Clinical characteristics of the study population are shown in LV end diastolic diameter index did not differ between the groups and LV EF was preserved in both study populations. LV S′ of the septal, lateral, inferior and anterior walls were significantly lower in haemodialysis patients. They had a significantly higher LV myocardial mass index (MMi) compared with the controls. LV hypertrophy was diagnosed in 25 (65.8%) haemodialysis patients. Haemodialysis patients had significantly lower E/A ratio and significantly higher E/e′ ratio compared with the controls. LV DD was found in 31 (81.6%) patients in the haemodialysis group: 24 (63.2%) had grade I DD and 7 (18.4%) had grade II DD. The LA volume index was significantly higher in the haemodialysis group and LA enlargement was diagnosed in 20 (54.1%) this group patients. Conventional echocardiographic characteristics of LV geometry and function in the study population are presented in RVD1 did not differ between the groups. The RA volume index was significantly higher in the haemodialysis group compared with the control group, as was the PA diameter. The parameters of the RV free wall longitudinal function were reduced in the haemodialysis group, however, no differences in the RV FAC were found between the groups. The haemodialysis group patients had significantly lower RV GLS and GLPSS values compared with the controls. Conventional echocardiography and STE characteristics of the RV in the study population are shown in Heart failure is associated with significant morbidity in ESRD patients undergoing haemodialysis, however, remains poorly characterized and not optimally treated because the dialytic cycle of volume accumulation between sessions and intra-dialytic extracorporeal ultrafiltration mask the clinical presentation of the heart injury . Previous studies revealed that conventional 2D echocardiography was not sensitive or specific enough to detect the early deterioration of cardiac function in patients with CKD ,14,15,16In the present study, speckle tracking 2D echocardiography demonstrated subclinical biventricular dysfunction in asymptomatic ESRD patients undergoing chronic haemodialysis. Changes of myocardial deformation parameters were found even when global LV EF and RV FAC  were preserved. Our study showed that patients with ESRD undergoing haemodialysis have significantly worse TDI S′ measurements and worse LV GLS, GLPSS, GCS and GCPSS at the mitral valve and papillary muscle levels when compared to controls. However, radial LV deformation was preserved at all short-axis levels, thus explaining the “normal” LV EF obtained by conventional 2D echocardiography using Simpson’s method.These results are similar with the data published by other authors. Kramman et al. demonstrated that STE could detect uraemia-related cardiomyopathy and predict CVD and all-cause mortality in patients with ESRD . Their sThe results of our study correspond to findings from previous studies and reveal that ESRD influences LV DD. During the progression of CKD, LV fibrosis leads to increased LV stiffness and LV filling pressure, causing impaired diastolic relaxation and DD ,25. The Previous studies showed that the incidence of LV hypertrophy varies from 70% to 90% in ESRD patients undergoing haemodialysis . The datRV dysfunction is a predictor of adverse outcomes in many heart diseases; however, there is a lack of data regarding the changes in RV geometry and function in patients with ESRD. Hickson et al. demonstrated that RV systolic dysfunction was relatively common (27%) in haemodialysis patients and was an important predictor of mortality . KaravelThe main limitations of this study were the small sample size, selection bias, the fact that 3D analysis of RV volume, RV EF and GRS were not evaluated. As most haemodialysis patients in our study had a radial AVF, LV and RV function could not be compared according to AVF types. Patients with ESRD and preserved LV ejection fraction undergoing haemodialysis have a higher prevalence of LV diastolic dysfunction, impaired LV longitudinal and circumferential deformation indices, as well as reduced RV longitudinal function and deformation parameters compared with age-matched healthy controls. STE helps to detect subclinical LV and RV dysfunction in chronic haemodialysis patients with preserved global biventricular function.


There are limited data on patients with leadless cardiac pacemakers (LCP) undergoing magnetic resonance imaging. The aim of this prospective, single-center, observational study was to evaluate artefacts on cardiovascular magnetic resonance (CMR) images in patients with LCP.Fifteen patients with Micra™ LCP, implanted at least 6 weeks prior to CMR scan, were enrolled and underwent either 1.5 Tesla or 3 Tesla CMR imaging. Artefacts were categorized into grade 1 , grade 2 (good), grade 3 (poor) and grade 4 (non-diagnostic) for each myocardial segment. One patient was excluded because of an incomplete CMR investigation due to claustrophobia.2) at the right ventricular (RV) apex. Of 224 analyzed myocardial segments of the left ventricle (LV) 158 (70.5%) were affected by grade 1, 27 (12.1%) by grade 2, 17 (7.6%) by grade 3 and 22 (9.8%) by grade 4 artefacts. The artefact burden of grade 3 and 4 artefacts was significantly higher in the 3 Tesla group . A high artefact burden was particularly observed in the mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV and in the mid and apical segments of the RV. Quantification of LV function and assessment of valves were feasible in all patients. We did not observe any clinical or device-related adverse events.LCP caused an arc-shaped artefact (0.99 ± 0.16 cmCMR imaging in patients with LCP is feasible with excellent to good image quality in the majority of LV segments. The artefact burden is comparable small allowing an accurate evaluation of LV function, cardiac structures and valves. However, artefacts in the mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV due to the LCP may impair or even exclude diagnostic evaluation of these segments. Artefacts on CMR images may be reduced by the use of 1.5 Tesla CMR scanners. Cardiovascular magnetic resonance (CMR) imaging, which has become a versatile, non-invasive imaging tool, allows a comprehensive evaluation of patients with cardiovascular diseases . The difPacemakers cause metallic susceptibility artefacts due to distortion of the magnetic field . There aFifteen patients with an LCP  implanted at least 6 weeks prior to CMR scan were enrolled in this prospective, single-center, observational study. Patients with other ferromagnetic implanted devices which may interact with the CMR scanner were excluded. The study participants were randomized in a 1:1 ratio into two groups: The study participants underwent CMR imaging in either a 1.5 Tesla CMR scanner  or a 3 Tesla CMR scanner  with a maximum gradient field of 45mT/m and a slew rate of 200 T/m/s. The Micra™ LCP is a MRI conditional single-chamber cardiac pacemaker and the device sizes 25.9 × 6.7 mm. LCP were interrogated before and immediately after the CMR scan and were programmed to an asynchronous, MRI conditional pacing mode  for the CMR scan. During the CMR scan patients were monitored by continuous electrocardiogram (ECG) and pulse oximetry. Blood pressure measurements were performed before and after CMR scans. An intercom was available for patient communication in the CMR scanners.The CMR protocol was conducted according to the recommendations of the Society for Cardiovascular Magnetic Resonance (SCMR) . We obtaAll available CMR images were reviewed by four experienced CMR observers (two cardiologists and two radiologists). In case of inter-observer differences in artefact quantification agreement was reached in case discussion. The LV was divided into 16 segments according to the American Heart Association (AHA) 16 myocardial segmentation classification system . The RV Grade 1: excellent image quality, no artefacts affecting myocardial segments or cardiac structuresGrade 2: good image quality with artefact adjacent to the myocardial segments or cardiac structures, delineation of myocardial borders may be limited, no impact on diagnostic valueGrade 3: artefact moderately affecting cardiac structures, less than half of the myocardial segment is superimposed by the artefactGrade 4: poor image quality with significant artefact affecting more than half of the myocardial segment, non-diagnostic imageLCP related artefacts were graduated as suggested by Klein-Wiele et al. :Grade 1:The artefact size was measured for every patient on short axis bSSFP cine images which showed the largest artefact. The artefact burden was calculated as affected myocardial segments by grade 1 (excellent), grade 2 (good), grade 3 (moderately) and grade 4 artefacts  divided by 224  for the LV and divided by 42  for the RV. The artefact burden ratio per patient was calculated as affected myocardial segments by grade 3 and 4 artefacts on 1.5 Tesla and 3 Tesla CMR images for the LV and RV.The study design was approved by the local ethics committee and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all study participants.p-value < 0.05 was considered statistically significant. All calculations were performed with SPSS statistical software .Categorical parameters are described as absolute number and percentage. Continuous values are presented as means ± standard deviation or means with 95% confidence intervals (95% CI). Differences between groups involving normally distributed data were analyzed by the unpaired t test; those involving not normally distributed data, by the Mann-Whitney U test; and those involving proportions, by the chi-square test. A two-sided n = 3) had a mean age of 77.8 ± 14.6 years and all of them had undergone implantation of a LCP at least 6 weeks prior the CMR scan. Indications for pacemaker implantation were bradycardic arrhythmias in permanent atrial fibrillation (n = 11) or third degree atrioventricular block (n = 3). Baseline characteristics of the study population including comorbidities are shown in Table Fifteen patients were enrolled in this prospective, single-center, observational study. The 1.5 Tesla and 3 Tesla group comprised seven patients each. One study participant was excluded from the study because of an incomplete CMR investigation due to claustrophobia. The remaining 14 patients . The artefact burden ratio per patient of affected myocardial segments by grade 3 and 4 artefacts on the short axis bSSFP cine images of the LV was significantly higher in the 3 Tesla group . The detailed analysis of myocardial segments affected by grade 3 and grade 4 artefacts revealed a high artefact burden particularly in the mid anteroseptal, inferoseptal and apical septal myocardial segments  with an artefact burden of 50, 50 and 85.7% in these regions, respectively. These artefacts were more pronounced in patients undergoing CMR on 3 Tesla CMR scanners . There were no artefacts in the basal inferoseptal, inferior, basal to apical anterolateral and inferolateral myocardial segments . Details of artefact distribution in the short axis are demonstrated in Fig. The LCP caused an arc-shaped artefact at the site of implantation of the RV apex Fig. . Of 224 n = 7, mildly impaired: n = 6, moderately impaired: n = 0, severely impaired: n = 1).Quantification of LV function and volumetry were feasible in 14 patients (100%) with a mean LV ejection fraction of 49 ± 7.4%. We experienced more problems of ECG-triggering in patients undergoing 3 Tesla CMR scans (3 Tesla vs 1.5 Tesla: 3 vs 0 patients). In one 3 Tesla patient, pulse-triggering was necessary for image acquisition. Analysis of the RV was evenly impaired in both cohorts due to artefacts of the LCP severely compromising the image quality of particularly the mid and apical free wall of the RV . The artefact burden ratio of affected myocardial segments by grade 3 and 4 artefacts on short axis bSSFP cine images of the RV revealed 1.1 ± 0.4 segments per patient. Therefore, an exact quantification of RV function was not possible in both groups and the RV function was only assessed visually . We did not observe any hemodynamically relevant tricuspid valve insufficiency in our study cohort of patients with LCP.p = 0.08) and a marginal, but statistically significant increase of sensing amplitude  and impedances . Battery voltage remained stable .There were no clinical or device-related serious adverse events during CMR scans. The CMR scans, both 1.5 and 3 Tesla, did not lead to malfunction of the implanted LCP devices. We observed no significant change of pacing thresholds . Artefacts occurred particularly in the mid anteroseptal, inferoseptal and septal apical myocardial segments  and in the mid and apical segments of the RV. 3 Tesla CMR imaging led to a significantly higher artefact burden ratio per patient compared to 1.5 Tesla CMR imaging. Assessment of LV function and aortic, mitral and tricuspid valve, as well as tissue characterization by T1- and T2- weighted imaging was feasible with both modalities.p = 0.02) and impedances . We do not consider these marginal changes to be clinically relevant because we did not observe any malfunction of LCP during or after CMR scans. Further studies are needed to provide follow up data of LCP after MRI.Several studies have demonstrated the safety and feasibility of MRI conditional, transvenous pacemakers and ICD undergoing MRI –11. Potep = 0.03). These susceptibility artefacts were pronounced in particular in the mid anteroseptal, inferoseptal and apical septal AHA myocardial segments 8, 9 and 14 of the LV and were even more pronounced in patients undergoing CMR on 3 Tesla. The RV was mainly affected in the mid and apical myocardial segments. The size of the arc-shaped artefact by the LCP (0.99 ± 0.16 cm2) was not significantly different in both groups . The size of the area affected by the artefact was 7-fold larger compared to the size of the LCP device itself. Quantification of LV function and volumetry were feasible in all patients (n = 14). However, the RV function could only be assessed visually, because of the high artefact burden, demonstrating 7 patients with normal, 6 patients with mildly and 1 patient with severely reduced RV function. However, the impaired RV function cannot be interpreted as a reduced RV function due to the LCP because we did not compare RV function before and after implantation of the LCP.Pacemakers and other implanted cardiac electronic devices lead to metallic susceptibility artefacts due to distortion of the magnetic field . ArtefacAs described above, mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV and mid and apical segments of the RV were affected by artefacts of the LCP in the majority of patients which may impair or even exclude diagnostic evaluation of these segments especially on perfusion and late gadolinum enhancement images. In contrast to our findings, Klein-Wiele et al. revealed in a population of 61 patients with MRI conditional, transvenous pacemakers no relevant artefacts in patients with right-sided devices irrespective of the imaging sequence . There wLCP are RV single-chamber pacemakers which are implanted by using a femoral percutaneous approach . The nexCMR is an important non-invasive imaging tool to assess patients with cardiovascular diseases by evaluating myocardial function, wall motion abnormalities, viability, coronary perfusion, valves and tissue characterization . Therefo2). Therefore, we conclude that the localization of the artefact depends mainly on the site of implantation of the LCP which is usually at the apex of the RV or at the apical or mid right interventricular septum. The impaired RV function in 7 patients of our study population cannot be interpreted as a reduced RV function due to the LCP because we did not compare RV function before and after implantation of the LCP. Furthermore, we were not able to report on late gadolinum enhancement sequences as these sequences were not part of our CMR scan protocol. As reported by Klein-Wiele, late gadolinum enhancement sequences showed a lower artefact burden compared to bSSFP cine images [Besides the limited number of patients this study has further limitations. This study enrolled only patients with Micra™ LCP and the described artefacts are specific for this LCP. Further studies are needed to evaluate the artefact burden of LCP from other manufactures. However, according to our data the size of the artefact by the LCP did not differ widely with only a small standard deviation on CMR images (0.99± 0.16 cme images .This prospective, single-center, observational study demonstrates that CMR imaging in patients with LCP implanted at least six prior to the CMR scan is feasible. Overall image quality was excellent to good in the majority of CMR images. Assessment of LV function and aortic, mitral and tricuspid valve as well as tissue characterization with T1 and T2 weighted imaging were feasible with 1.5 Tesla and 3 Tesla. However, mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV were affected by artefacts of the LCP in the majority of patients which may impair or even exclude diagnostic evaluation of these segments. Artefact burden on CMR images may be reduced by the use of 1.5 Tesla scanners.


Reliable evaluation of the severity and consequences of pulmonary regurgitation (PR) in patients with repaired tetralogy of Fallot (TOF) is crucial to timely identify the need for pulmonary valve intervention. We aimed to identify the accuracy of echocardiographic parameters to differentiate between moderate and severe PR, using phase contrast cardiac magnetic resonance imaging (CMR) as gold standard.In this cross‐sectional study, 45 TOF patients with both echocardiographic and CMR measurements of PR were enrolled. All quantitative and semiquantitative echocardiographic measurements such as pressure half time (PHT), Color flow jet width (CFJW), ratio CFJW/right ventricle outflow tract (RVOT) diameter, PR index and the presence of early termination of the PR jet, end‐diastolic antegrade flow and diastolic backflow in main pulmonary artery (MPA), and PA branches correlated significantly with PR fraction on CMR. Qualitative assessment with color flow on echocardiography overestimated PR Multivariate linear regression analysis identified the ratio of CFJW/RVOT diameter and PHT as independent predictors of PR fraction. Accuracy of echo parameters was tested to differentiate between mild‐to‐moderate and severe PR Combining different echocardiographic parameters increased sensitivity and specificity. The addition of diastolic flow reversal in the PA branches to PHT below 167 milliseconds increased the NPV from 87% to 89% and PPV from 62% to 76%.Comparison with CMR confirms that echocardiographic parameters are reliable in predicting PR severity. Combined measurement of diastolic flow reversal in the pulmonary artery branches and PHT is reliable in the detection of severe PR in the follow‐up of TOF patients. Details of the MR sequence used have been reported previously.2.4P value of less than .1 in univariate analysis) were added to the multivariable model. The multivariable model was tested for collinearity (variance inflation factor [VIF] score). A linear regression of PR fraction from CMR with the ratio CFJW/RVOT diameter and CW Doppler PHT to identify clinically meaningful cutoff points at, respectively, 20 and 40% PR measured on CMR. Patients were categorized according to the regurgitation fraction (RF) calculated on CMR into 3 categories: mild (<20%), moderate (20%‐40%), and severe (>40%). The kappa coefficient was calculated to assess the agreement between visual assessment of PR and PR measured with CMR. Proportions in mild to moderate versus severe PR were compared using Fisher’s exact test. Sensitivity, false‐positive rate (1‐specificity), positive predictive value (PPV), and negative predictive value (NPV) of echocardiographic parameters to grade PR using the RF found on CMR (dichotomized at 40%) as the gold standard were calculated for each echocardiographic parameter.Continuous data are presented as mean ± standard deviation (SD) or median with interquartile ranges when appropriate. Categorical variables are presented as frequencies and percentages. To quantify correlations, we used the Pearson correlation test for continuous variables or Spearman rank correlation test when appropriate. Multivariate linear regression analysis according to the stepwise method was performed for associations between echocardiographic parameters and PR fraction calculated with CMR. The following 5 parameters: ratio CFJW/annulus, PHT, time pulmonary insufficiency in diastole, antegrade flow end‐diastolic, and retrograde flow in PA branches  were considered to be statistically significant. Statistical analysis was performed using the statistical packages IBM SPSS Statistics version 21.0 .An interobserver reproducibility assessment was performed on 20 randomly selected patients for the RVOT diameter, CFJW, ratio CFJW/RVOT, and PHT using the Bland‐Altman method. The coefficient of variability was calculated as the standard deviation of the difference of the two measurements divided by the mean of the two measurements, and multiplied by 100%. 33.1The baseline characteristics of the 45 patients with repaired TOF included in this study are summarized in Table Mean peak systolic velocity of the pulmonary valve of the total population was 2.2 ± 0.8 m/s including mild PV stenosis in 15 (33%), a moderate PV stenosis in 7 (16%), and a severe PV stenosis in 1 (2%) patient. Right ventricular (RV) function (available for 39 patients) was found normal in 15 patients (33%), mildly impaired in 18 patients (40%), and moderately impaired in 6 (13%) patients. Quantitative RV evaluation demonstrated a reduced RVFAC <35% in 8 patients indicating preserved RV function in the majority of patients (Table 3.2P < .01)  according to PR fraction measurement on CMR . An overview of the differentiate capacity and the predictive values of all echocardiographic parameters are listed in Table The presence of diastolic flow reversal in the main PA and in the PA branches, had excellent sensitivity and NPV to identify severe PR However, specificity values are rather low. PHT on the contrary shows excellent specificity of 100% and a PPV of 100%. Based on the linear regression analysis, the optimal cutoff value to detect severe PR at 40% in our study population is a PHT of less than 167 milliseconds Figure . Using tThe ratio of the CFJW over RVOT diameter showed good correlation with PR fraction Table . To testFigure 4This study aimed to evaluate the accuracy of 10 different echocardiographic parameters in the assessment of PR severity in the operated adult TOF population. First, PR is highly prevalent with moderate to severe PR being present in 67% of patients. Second, qualitative assessment of PR on echocardiography is good, but overestimates moderate PR Third, all 10 investigated quantitative and semiquantitative echocardiographic measurements are accurate to detect severe PR Fourth, combining different echocardiographic parameters increased sensitivity and specificity. As such, the combination of diastolic flow reversal in the PA branches and short PHT is suggested as the best, ready to use and reliable measurement to identify severe PR in TOF patients.Different cutoff points of PR fraction on CMR have been used to quantify PR with a PR fraction of >20% considered as hemodynamically significant PROur study demonstrates that the presence of backflow from the PA branches is an excellent and accurate parameter to identify severe PR Flow reversal from the PA branches, indicating a larger volume of flow from further downstream, is not only intuitively but also statistically more accurate in detecting severe PR compared with flow reversal in the MPA. These findings are in line with flow reversal from the descending aorta in severe aortic regurgitation and have been demonstrated previously.PHT appeared to be a good predictor of severe PR, both as a continuous and dichotomous variable.5Evaluation with color flow over PV, PA, and PA branches from the parasternal short‐axis view at the level of the aortic valve.If no backflow from the PA branches is present, we can exclude severe PR.If diastolic flow reversal from the PA branches is present, we can further differentiate between moderate and severe PR using continuous wave Doppler analysis. If both backflow in PA branches is visualized and PHT is short, severe PR is present.Echocardiography is recommended as first‐line diagnostic method for initial and longitudinal assessment of PR in TOF patients.Careful follow‐up should be organized in patients with severe PR However, the prognostic value and implications on clinical follow‐up  and frequency of follow‐up visits need to be evaluated in a prospective follow‐up study and larger patient population.6The following limitations need to be acknowledged. Firstly, the sample size is limited and secondly, this is a cross‐sectional study which implies that clinical implications of the described findings need to be evaluated in a large, prospective follow‐up study. Thirdly, the median interval between the echocardiogram and CMR exam was 1.5 months. The study population included 2 outliers with, respectively, 353 and 368 days between both exams. Both patients, however, had an echocardiogram one year before and one year after the CMR. As the severity of the PR on echocardiogram had not changed through these 2 years  the patients remained in the study cohort. Although no significant clinical changes were noted during the interval, it is possible that the severity of PR may have varied in relation to their hemodynamic state.7This study demonstrates that echocardiography is accurate in predicting PR severity in the follow‐up of TOF patients. In particular, straightforward measures including the presence of diastolic flow reversal from the PA branches and a PHT <167 milliseconds are able to differentiate mild‐to‐moderate from severe PR Although each of the investigated parameters showed excellent correlation with the CMR PR fraction, a combination of different parameters further improved the accuracy and differentiates from restrictive RV physiology. The calculated cutoff value of PHT as well as the suggested flow chart requires further validation in a larger study population prior to the clinical application.The authors declare that they have no conflict of interest with the contents of this article.All authors had substantial contributions to the research design, data acquisition, analysis or interpretation, revised the manuscript, and gave their approval for submission of the finale version.Concept/design: An Van Berendoncks, Jackie McGhie, Jolien W Roos‐Hesselink; Annemien E van den BoschData analysis/interpretation: An Van Berendoncks, Roderick Van Grootel, Jackie McGhie, Annemien E van den Bosch Drafting article, An Van BerendoncksCritical revision of article: Roderick Van Grootel; Jackie McGhie, Judith A A E Cuypers; Ad J J C Bogers, Maarten Witsenburg, Jolien W Roos‐Hesselink, Annemien E van den BoschStatistics: An Van Berendoncks; Roderick Van GrootelData collection: Jackie McGhie; Matthijs van Kranenburg, Myrthe Menting; Judith A A E Cuypers.


Conclusions: Inadequately low LVM relative to the individual hemodynamic load could potentially reflect a different mode of the LV response to severe AS, associated with enhanced load-independent LV systolic performance, i.e., better LV contractility. If confirmed in a large series of patients, our small preliminary study may add to the possible mechanisms of a previously reported counterintuitive tendency of a lower, not higher, risk of adverse outcome in patients with low LV mass despite severe AS. Prospective studies are warranted, in order to determine a potential utility of LVM inadequacy in the risk stratification of patients with AS.Background: Left ventricular hypertrophy (LVH), traditionally considered an adaptive mechanism that is aimed at the maintenance of LV systolic function, is absent in 10%–35% of patients with severe aortic stenosis (AS). Our aim was to estimate the clinical and hemodynamic characteristics in patients with severe AS and absent LVH, or inadequately low LV mass (i-lowLVM) relative to an individual hemodynamic load. Methods: We retrospectively analyzed in-hospital records of 100 patients with pure severe degenerative AS, preserved LV systolic function and without relevant coexistent diseases, except for well-controlled hypertension or diabetes. Results: Clinical characteristics were similar in patients with and without LVH, as well as those with and without i-lowLVM, except for slightly lower GFR at i-lowLVM. When compared to their counterparts, subjects without LVH or with i-lowLVM had smaller LV cavities, decreased LV wall thicknesses and higher EF. There were no significant differences in stenosis severity and indices of afterload , according to the presence or absence of either LVH or i-lowLVM. However, LV fractional shortening at the midwall level was elevated only in patients with i-lowLVM, but not in those without LVH, compared to the remainder (15.8 ± 3.3 vs. 12.9 ± 3.2%,  Left ventricular hypertrophy (LVH), traditionally considered an adaptive mechanism that is aimed at the maintenance of LV systolic function, is absent in 10%−35% of patients with severe aortic stenosis (AS) ,3,4, theMoreover, patients with inadequately low LV mass (i-lowLVM), i.e., observed LV mass (LVM) in the lower part of the distribution of the value predicted from an individual hemodynamic load, had either a similar  or lowerNotably, only a few studies have been focused on characteristics of patients with low LVM, despite severe AS ,2,3,4. T2/m2 or mean transvalvular pressure gradient >40 mmHg) without relevant coexistent diseases, except for well-controlled diabetes or hypertension, with preserved LV ejection fraction (≥50%) [2 (by the CKD-EPI formula), was reported earlier in detail [We retrospectively analyzed in-hospital records of patients with pure severe degenerative AS  . A compln detail . Besidesn detail , additiomax) [max) by a previously validated formula [measured (g) = 0.8 × (1.04 × (((LVd + IVSd + PWd)3 − LVd3))) + 0.6, where LVd is the LV internal diameter, IVSd is the interventricular septum thickness, and PWSd is the posterior wall thickness  [predicted (g) = 55.37 + (0.009216 × (stroke volume (mL)) × (SBP + APGmax (mmHg))) + (6.63 × (height (m))2.7) − (18.1 − n), with n = 1 for men and n = 2 for women [measured − LVMpredicted)/LVMpredicted) × 100% [measured >95 g/m2 for women and >115 g/m2 for men), was absent in 23% of our patients, for consistency, we assumed i-lowLVM as an eLVM below the 23th percentile of its distribution  in the study population. In addition to the indexation of LVM for body-surface area, we also repeated the analysis after the LVM normalization for height to the power of 2.7, as previously proposed [From routinely recorded parameters of LV structure and function, we calculated LV fractional shortening at the midwall level (mwFS), assuming a constant volume of the inner myocardial “shell” between the LV midwall and the endocardium, according to a simplified spherical LV model ,17. Addimax) ,18,19,20max) . Then, wmax) ) and tha formula ,24. Accod in cm) , while Lor women ,24. The t-test or the Mann–Whitney U-test, and Fisher’s test for continuous and categorical data, respectively. A Bonferroni-corrected p-value <0.05 was inferred significant, which corresponds to a pre-adjusted p-value <0.002.Data are shown as means and SD, or medians and interquartile range, and numbers with percentages. The analyzed subjects were compared according to the LVH presence or the LVM inadequacy by a 2-tailed Student’s Clinical characteristics were similar in patients with and without LVH by the classical mass criteria, as well as with and without i-lowLVM relative to the individual hemodynamic load, except for slightly lower GFR in those with i-lowLVM .When compared to their counterparts, subjects without LVH or with i-lowLVM had smaller LV cavities, decreased LV wall thicknesses, and higher EF . There wThe results were virtually unchanged when the LVH definition was based on the indexation of LVM for height instead of for body surface area.Our salient observation was an association of LVM inadequacy, but not LVH absence, with better LV systolic performance at the midwall level in severe AS. In addition, cESS and Zva—indices of afterload—were similar, while LV diastolic diameter, a raw measure of preload, was lower in AS patients with i-lowLVM than in their counterparts. Accordingly, this constellation of findings suggests that a load-independent increase in LV function, i.e., improved LV contractility, may be specific for AS subjects with i-lowLVM, and not for those with absent LVH.Patients without LVH had smaller LV cavity sizes and thinner LV walls, as well as higher EF when compared to those with LVH, in agreement with previous reports ,2,4. BarIn contrast, patients with i-lowLVM exhibited increased both EF and mwFS in comparison to their counterparts, with a ratio of measured to predicted LVM above the 23th percentile of its distribution in the study population. This appears to be partially analogous to an early report by De Simone et al.  who descNotably, excessive LVH, i.e., inappropriately high LVM out of proportion to LV afterload, is associated with depressed mwFS, despite a lower or unchanged cESS, indicating depressed LV myocardial performance in patients with mild-to-severe AS ,19,20, wThe enhanced LV contractile function might be protective against LV dysfunction in severe AS with i-lowLVM. In accordance with this hypothesis, Kupari et al.  observedDue to a paucity of studies, determinants of absent LVH and especially i-lowLVM still remain unexplored. In agreement with earlier observations ,2, the pFirst, a retrospective design and a relatively low number of patients are major limitations of our report. However, exclusively subjects without coexistent diseases, including CAD, were entered into the final analysis, in order to reduce the heterogeneity of the study group. Second, the individual hemodynamic load was estimated on the basis of in-hospital BP recordings and echocardiography, while averaged values over a long period of time would be more appropriate. Nevertheless, we analyzed only patients with well-controlled hypertension and stable BP, which suggests that the computed parameters could be, to some degree, representative for a given subject. Third, medical therapy, which is known to affect LVM, was not uniform. However, the proportions of patients treated with renin–angiotensin system inhibitors, drugs with a well-recognized ability to attenuate LVH, were similar, according to LVH presence or LVM inadequacy.Keeping in mind the limitations of our small retrospective study, inadequately low LVM relative to the individual hemodynamic load could potentially reflect a different mode of LV adaptation to AS, associated with enhanced load-independent LV systolic performance, i.e., better LV contractility. If confirmed in a large series of patients, our preliminary report might add to the possible mechanisms of a previously reported counterintuitive tendency of a lower, not higher, risk of adverse outcome in patients with low LV mass, despite severe AS. Prospective studies are warranted in order to determine a potential utility of LVM inadequacy for the prediction of clinical outcomes and risk stratification of patients with AS.