To develop a high temporal resolution phase‐contrast pulse sequence for evaluation of diastolic filling patterns, and to evaluate it in comparison to transthoracic echocardiography.A phase‐contrast velocity‐encoded gradient‐echo pulse sequence was implemented with a sector‐wise golden‐angle radial ordering. Acquisitions were optimized for myocardial tissue  and transmitral flow . Shared velocity encoding was combined with a sliding‐window reconstruction that enabled up to 250 frames per cardiac cycle. Transmitral and myocardial velocities were measured in 35 patients. Echocardiographic velocities were obtained with pulsed‐wave Doppler using standard methods.2 = 0.63). Transmitral velocity was underestimated by MRI (P < .05) with a difference of −11 ± 28 cm/s (R2 = 0.45). The early‐to‐late ratio correlated well (R2 = 0.66) with a minimal difference (0.03 ± 0.6). Analysis of interobserver and intra‐observer variability showed excellent agreement for all measurements.Myocardial velocity showed a low difference and good correlation between MRI and Doppler (mean ± 95% limits of agreement 0.9 ± 3.7 cm/s, RThe proposed method enables the acquisition of phase‐contrast images during a single breath‐hold with a sufficiently high temporal resolution to match transthoracic echocardiography, which opens the possibility for many clinically relevant variables to be assessed by MRI. Heart failure can be classified as heart failure with reduced ejection fraction (HFrEF), in which the left ventricular systolic function is decreased and CMR is a valuable imaging modality for diagnosis and follow‐up, or in heart failure with preserved ejection fraction (HFpEF). In the latter, the pathophysiological mechanisms are debated,The evaluation of diastolic function requires a joint assessment of several cardiovascular parameters, but some key variables are pulsed‐wave Doppler measurements of peak blood in‐flow velocity through the mitral valve in early (E) and late (A) diastolic filling and pulsed‐wave tissue Doppler measurements of the peak myocardial tissue velocity in the early filling phase (e′). In addition, the peak myocardial velocity in systole (s′) and the peak myocardial velocity in the late diastolic filling phase (a′) may be of interest. As the period of maximum velocity is very short, and the current guidelines by the American Society of Echocardiography and the European Association of Cardiovascular Imaging specify absolute cut‐off values for these parameters,As it stands, CMR offers inferior temporal resolution to TTE.A promising method for enabling high temporal resolution CMR is the so‐called golden‐angle method.In the present work, we propose a sector‐wise golden‐angle (SWIG) radial profile ordering, that is based on the segmented golden ratio ordering,22.1s = 0, 1, 2, …, N was the current heartbeat obtained from the electrocardiogram, N was the desired number of heartbeats to be acquired, and nϕ was the nth azimuthal angle. The profile ordering was updated on the fly, so that 1 sector was acquired per RR interval. Before image reconstruction, the first heartbeat (s = 0) was discarded to ensure complete steady state of the longitudinal magnetization. This radial ordering resulted in k‐space spokes remaining approximately equidistant for an arbitrary number of spokes, even after retrospective electrocardiogram gating.M1) velocity‐encoded scheme centered around M1 = 0 mT ms2 m−1, such that every other readout had alternating positive and negative M1 of equal magnitude.A common gradient‐echo pulse sequence (FLASH) was modified to enable radial sampling with the proposed SWIG method Figure . By divi2.2temporal footprint and temporal increment. The temporal footprint was defined as the number of k‐space spokes used to reconstruct 1 phase‐subtracted image. The temporal increment was defined as the spoke increment between window positions . The theoretical limit for the temporal footprint for a phase‐contrast pulse sequence was therefore 2 TRs  per heartbeat, and the corresponding limit for the temporal increment was 1 TR  per heartbeat. Given a typical breath‐hold duration of 13 heartbeats, the minimum number of k‐space spokes per reconstructed phase‐subtracted image frame was 26 spokes.Previous studies have shown that the most important parameter when determining peak velocities is temporal resolution,2.32, and receiver bandwidth = 1560 Hz/pixel. The study was performed in agreement with the Helsinki Declaration and approved by the regional ethics board. Written, informed consent was obtained from all subjects.To investigate whether the SWIG method alone could achieve a sufficiently short temporal footprint without temporal regularization or other constraints, an initial pilot study was designed with 10 subjects  who underwent both CMR at 1.5 T  and TTE within 24 hours. Myocardial tissue velocities were measured in a basal short‐axis slice with through‐plane velocity encoding acquired during a single breath‐hold acquisition with the previously described SWIG pulse sequence. Relevant parameters were TE/TR = 4.4/6.8 ms, flip angle = 8º (Ernst angle), velocity encoding (VENC) = 30 cm/s, 13 heartbeats, matrix size = 64 × 64 pixels, FOV = 320 × 320 mm2.42, bandwidth = 1560 Hz/pixel) and transmitral flow . No echo asymmetry was used in either of the acquisitions. All subjects in the main study population underwent standard‐of‐care TTE on clinical indication, with a median time between TTE and CMR of 4 days (interquartile range 19 days) with 25% of subjects undergoing both CMR and TTE within a 24‐hour period. The study was performed in agreement with the Helsinki Declaration and approved by the regional ethics board. Written, informed consent was obtained from all subjects.Patients  with various pathologies underwent MRI at 1.5 T or 3 T . All patients had normal sinus rhythm. The protocol was similar to what was previously described in the temporal resolution study, but included a second acquisition of the transmitral blood flow velocity. For ease of planning and reproducibility, both measurements were performed in the same slice position, at the tip of the mitral leaflets in systole. The acquisitions were optimized for myocardial tissue , VENC = 30 cm/s, 13 heartbeats, slice thickness = 5 mm, matrix size = 64 × 64 pixels, FOV = 320 × 320 mm2.5The total number of frames to be reconstructed was determined by dividing the duration of the shortest heartbeat by the temporal increment, in TRs. The heartbeats were then linearly stretched to a common temporal axis, and the number of frames to be reconstructed was placed equidistantly on the common temporal axis. The temporal increment was fixed to 1 TR for all reconstructions, which resulted in a typical number of reconstructed phase‐contrast images ranging from 150‐250 frames, depending on the heart rate of the subject. Each k‐space line was matched to its corresponding cardiac phase through nearest‐neighbor matching, such that no temporal interpolation of k‐space lines was necessary.shared velocity encoding.ϕ is the phase difference, and Z1 and Z2 are a pair of complex images. By performing the phase subtraction according to Equation π was avoided.For the pilot study, multiple sets of phase‐contrast image series were reconstructed with temporal footprints corresponding to 4, 6, 8, 10, and 12 spokes. When combining a symmetric velocity encoding with sliding‐window reconstruction, it is possible to reduce the temporal increment to 1 TR by using the so‐called Receiver coil sensitivity maps were estimated using an adaptive coil combination method,2.6To evaluate the potential benefit of the SWIG method over a conventional golden‐angle profile ordering, both orderings were calculated for each acquisition and physiological resorting was performed equally. The point spread function (PSF) was calculated by gridding of a unitary k‐space, and the PSF was resampled on concentric circles with increasing radius. The aliasing energy, defined as the sum of square of the PSF values on each circle as well as the peak PSF value, was determined as a function of the radius.2.7All reconstructed images were exported from MATLAB as DICOM files and imported into the freely available image analysis software package Segment v2.1 R6069 .2.8The median heart rate and heart rate variability, expressed as the SD of the RR intervals, were extracted from the stored electrocardiogram trace of each subject. The measurement bias was obtained from Bland‐Altman analysis of the TTE and CMR measurements. Linear regression was used to assess whether the bias was associated with either heart rate or heart‐rate variability.2.9To characterize the degree to which eddy currents affected the measurement, a phantom experiment was performed on a spherical phantom (240 mm in diameter), which was placed in the isocenter of a 1.5T scanner (MAGNETOM Aera) and was scanned with the proposed SWIG method using the same protocol as in the previous experiments, with VENC at both 30 cm/s and 150 cm/s. The images were reconstructed as previously described, but with a larger temporal footprint to improve SNR. In addition, a Cartesian phase‐contrast pulse sequence with symmetric velocity encoding was used for comparison, and the images were reconstructed using the vendor‐provided reconstruction on the scanner. The scan parameters were matched as closely as possible between both sequences. Residual phase errors after phase subtraction were measured as the mean absolute phase deviation over the phantom. Quadratic phase‐error correction was performed as previously described, and the residual phase error was measured again.2.10Interobserver and intra‐observer agreement was assessed by 2 experienced observers (A.F. and J.G.R.) on a subgroup consisting of 10 patients with a representative distribution between images acquired at each field strength. Both observers had been trained in CMR analysis of myocardial and blood velocities using the software plug‐in being used. Interclass correlation (ICC) was calculated, and the results were graded according to the guidelines from Cicchetti.3The characteristics of the study population are outlined in Table 3.1Representative examples of profile distributions after physiological resorting for the SWIG and conventional golden‐angle methods are found in Figure 3.2Phase‐contrast SWIG CMR showed high correlation with tissue Doppler across a wide range of temporal footprints when comparing early‐filling tissue velocity in the lateral wall. The velocities did not differ between phase‐contrast CMR and Doppler for temporal footprints between 40.8 ms and 81.6 ms. The results from the temporal resolution study are summarized in Table 3.32 = 0.63). All data points for the myocardial velocity measurements, along with the corresponding Bland‐Altman plots, are displayed in Figure P < .05), with a bias of −11 cm/s (limits of agreement ± 28 cm/s) and a correlation of R2 = 0.45. The early‐to‐late (ratio correlated well (R2 = 0.66) with a minimal bias of 0.03 cm/s (limits of agreement ± 0.06 cm/s). All data points for the transmitral blood flow velocity measurements, along with the corresponding Bland‐Altman plots, are displayed in Figure Based on the results from the temporal resolution pilot study, the final temporal resolution was selected to be 6 TRs, corresponding to a temporal footprint of 40.8 ms for the myocardial tissue velocity measurements and 39.6 ms for the transmitral blood flow measurements. In terms of undersampling, each image was reconstructed from 36 radial spokes, which corresponds to an undersampling factor R = 2.8 with respect to the radial Nyquist limit. This footprint represents the narrowest footprint at which phase‐contrast CMR and TTE did not differ  or heart‐rate variability   nor heart rate variability   beats/minute during the myocardial velocity measurements and 67 (58.2‐75.8) beats/minute during the transmitral velocity measurements. The median heart‐rate variability was 17 (7‐28) ms and 21 (9‐33) ms for the 2 measurements, respectively. For myocardial tissue velocity, no correlation was observed between measurement bias and heart rate  for Cartesian and 0.30 cm/s (mean 0.10 cm/s) for SWIG, and for VENC = 150 cm/s, 0.19 cm/s (mean 0.05 cm/s) for Cartesian and 0.38 cm/s (mean 0.10 cm/s) for SWIG.3.6The analysis of interobserver agreement showed good agreement (ICC = 0.62) for the myocardial tissue velocities and excellent agreement (ICC = 0.95) for the transmitral blood flow velocities. The corresponding Dahlberg errors where 2.18 cm/s (RDE = 22%) for myocardial tissue and 3.5 cm/s (RDE = 8%) for the transmitral flow.3.7The analysis of intra‐observer agreement showed excellent agreement for both the myocardial tissue velocities (ICC = 0.89) and for the transmitral blood flow velocities (ICC = 0.97). The corresponding Dahlberg errors where 1.09 cm/s (RDE = 11%) for myocardial tissue and 2.97 cm/s (RDE = 6%) for the transmitral flow.4The main finding of this study is that an efficient CMR pulse sequence can acquire phase‐contrast images during a single breath‐hold with a sufficiently high temporal resolution to match TTE. This finding challenges the perceived idea that CMR is a slow modality, and opens the possibility for many clinically important variables, which previously have been exclusive to TTE, to be assessed by CMR.In this work, we implemented and investigated a radial sector wise golden‐angle profile ordering for high frame rate phase‐contrast VENC imaging of the heart, with the purpose of determining diastolic dysfunction parameters that were previously unattainable by CMR. Radial k‐space sampling updates the k‐space center each TR, in contrast to Cartesian acquisitions, which only updates the k‐space center once per segment. This conceptual difference in k‐space acquisition may affect the ability to resolve velocity peaks and sensitivity to beat‐to‐beat variations. When analyzing the bias, no dependence on neither heart rate nor heart‐rate variability could be observed in our cohort, but further investigation is justified, particularly at heart rates over 90 bpm. The method could potentially be improved by using nonlinear scaling of the heartbeats during image reconstruction.M1. This problem can be alleviated by a simple shifting of M1The analysis of the interobserver and intra‐observer agreement showed good to excellent agreement, which along with the small RDE, suggested that the method is highly reproducible. However, the slightly lower agreement for myocardial tissue velocity may be a reflection of the noisier data observed for myocardial tissue Figure . The mea2 = 0.34, mean difference = −2.3 cm/s, 5.3 cm/s). The error was potentially compounded by simultaneous overestimation of e′ and underestimation of E.In general, myocardial velocities measured by CMR were slightly higher than those measured by TTE. Although this finding is interesting, no conclusions can be made without an external reference measure, such as sonomicrometry in a phantom or animal model. Early filling myocardial velocity (e′) is of special interest in the evaluation of diastolic function in the clinical settings, as it is a key parameter in the E/e′ ratio, which is used as an indicator of elevated left ventricular feeling pressure. The agreement between E/e′ by TTE and CMR was modest (RM1 values for each TR, potentially leading to unwanted phase‐cancellation effects. In general, the myocardial tissue time‐velocity curves tend to be sharper and therefore more demanding of small temporal footprint compared with the transmitral time‐velocity curves, which suggests that the reason for underestimation of transmitral flow is not due to a lack of adequate temporal resolution. In addition, the excellent interobserver agreement further suggests that the reason for the observed bias cannot be explained by the analysis.The finding that CMR tended to underestimate transmitral blood flow warrants further investigation. The reason for this underestimation is yet to be established, but a possible explanation is that the measurement slice has been placed too far apically in relation to the mitral leaflets, resulting in suboptimal placement of the measurement volume. To more accurately place the measurement volume, a long‐axis view could be acquired with in‐plane VENC to alleviate this challenge, similar to ultrasound. Implementing radial in‐plane encoding is challenging, as the k‐space center will have different The analysis of the PSF suggested that the SWIG method resulted in a more even k‐space coverage after physiological re‐sorting than the conventional golden‐angle ordering. However, a number of optimizations remain to be explored. In Equation In conventional tissue phase mapping, blood suppression is commonly used for better delineation of the myocardium and reduction of flow artifacts caused by beat‐to‐beat velocity variations by spatial saturation adjacent to the imaging slice, to saturate in‐flowing blood. Previous studies have shown improved reproducibility of myocardial tissue motion measurements from blood suppression with Cartesian phase contrast by reducing flow artifacts,Another effect worth considering is eddy currents. When reconstructing a VENC image, the phase effects caused by gradients common in both encodings will be subtracted. The analysis of eddy currents showed that the SWIG method did not result in a larger phase error than a conventional Cartesian phase‐contrast pulse sequence, and after the quadratic phase offset the correction residual phase error was less than 1% for both sequences.Future development could use a spatial frequency‐dependent temporal filter5The SWIG method enables a considerable improvement in temporal resolution compared with previous methods. We have demonstrated that the SWIG method is capable of measuring left ventricular myocardial tissue velocity and transmitral blood flow velocity with high correlation and low‐to‐moderate bias when compared with TTE, in a single breath‐hold acquisition, making CMR a promising method for diastolic dysfunction evaluation.


Purpose: Physical activity (PA) is considered essential for the treatment of morbid obesity and the optimization of bariatric surgery outcomes. The objective of this article was to identify the facilitators and barriers that bariatric patients perceived to do PA one year after finishing a PA programme for the promotion of a long-term active lifestyle. This objective was addressed from a socio-ecological and qualitative perspective.Methods: Nine patients (eight women and one man), aged between 31 and 59 years, participated in semi-structured interviews directly following the PA programme and one year after it. A content analysis was carried out to analyze the qualitative data.Results: Weight loss, improvement of physical fitness, perceived competence, and enjoyment were the main facilitators of PA. Complexes related to skin folds, osteoarthritis, perceived unfavourable weather conditions, lack of social support and economic resources, long workdays, lack of specific PA programmes, and other passive leisure preferences were the main barriers to participate in PA.Conclusions: Results highlight the important interplay between personal, social environmental, and physical environmental factors to explain (in)active behaviours of bariatric patients. The findings of this article could be useful for future research and interventions aimed at promoting PA in bariatric patients. This PA programme included a motivational intervention for the promotion of a sustained active lifestyle (see Methods).2.2.1.M = 46.77, SD = 9.75), who attended a PA programme one month after receiving bariatric surgery. They were mostly women .The participants in this qualitative study were nine patients aged between 31 and 59 years . The economy of this city is mainly dependant on the footwear industry and tourism. The majority of population pertain to a middle socioeconomic status.2.2.The PA programme took place in a public fitness centre located in Elche and lasted six months. The instructors were exercise and sport sciences professionals , who were trained in strategies based on SDT . The PA programme was evaluated and approved by a medical council formed by doctors, surgeons, endocrinologists, nutritionists, psychologists, psychiatrists and exercise science professionals. Participants were informed about the aims and procedure of the study and provided written consent. In-depth semi-structured interviews were conducted and recorded with each participant to gather qualitative information. The interviews took place in a quiet room at the first author’s research centre. Firstly, semi-structured interviews were conducted just after the PA programme (July 2012). These interviews were conducted, regarding the purpose of this article, to know if the participants had the intention of participating in PA in the future, after the end of the PA programme. Secondly, semi-structured interviews were conducted again one year after the end of the PA programme (July 2013) with the same patients with the dual purpose of (1) knowing if participants had performed PA during that year and (2) identifying the factors that favoured or hindered their participation in PA during the year. The interviews lasted between 40 and 60 minutes. An example of the initial questions guiding the first and second interviews is shown in 2.3.Semi-structured interviews were transcribed by the interviewer with a word processor software immediately after conducting them. Transcriptions were analyzed with the support of the software NVivo, which was used to organize and classify data efficiently  and “directed” (deductive) content analysis  Bariatric patients’ intention of participating in PA just after the PA programme; 2) Facilitators to PA one year after the end of the PA programme; and 3) Barriers to PA one year after the end of the PA programme. These categories, with their corresponding subcategories, are described and discussed in the following sections.3.1.Telma:I’m sure that exercise will be part of my life. In fact, I have already bought a bike for me. And I have started to walk and even run, something I had never done in my life. Because I don’t want to get fat again. I’ve not doubt about it. Would I go back to the way I was? No way!Just after the PA programme, all bariatric patients who participated in this study reported their intention of engaging in PA in the future:Pam:They [instructors] have given us all the options. Whoever doesn’t want to do physical activity now, it’s because they don’t want to. You cannot say: “Oh, I don’t have money to go to the gym!” Well, you don’t have money to go to the gym, but you can do it on the street.It is also noteworthy that all participants argued that the programme had given them sufficient knowledge to do PA without having large resources or without joining a gym, because of all the talks, advice and practical sessions that the instructors provided them:From a socio-ecological perspective, the intention to be active and having knowledge to be active are two personal factors related to PA participation, as other studies have pointed out  benefits can also favour a better interaction with the social environment and a higher involvement in social activities which can involve PA.3.2.2.From a socio-ecological perspective, social support is considered an important socio-environmental factor that fosters PA . Although summers are hot, the weather does not seem to be a real barrier to do PA for the most part of the year.Difficulties with coping with the weather have been reported by bariatric patients in previous studies, but these barriers to PA seem to be more related to a “mental obstacle” than to important physical environmental barriers . Unfortunately, after a deliberate six months of intervention, the programme of the study ended, and the participants expressed their concern:The participants of our study thought that attending sport and PA facilities was expensive, in line with previous research with bariatric patients  and environment  played a major role in the consolidation of (in)active lifestyles. A qualitative socio-ecological perspective was useful to identify the interrelated influence of personal, social environmental and physical environmental factors on PA participation.The qualitative design and small sample of our study were not aimed at generalizing results. However, our qualitative design let the collection of in depth information about the participants, and content analysis made possible the emergence of insights which can be transferable and useful for future research and interventions aimed at promoting PA in bariatric patients.After the PA programme, all patients intended to be physically active in the future and argued to have enough knowledge to do PA on their own. Nevertheless, one year later, our results pointed out that the move from an intention to the actual behaviour of PA is a difficult step to take.Weight loss and maintenance, coupled with perceived improvements in physical fitness, gave rise to a greater perception of physical competence, greater enjoyment with PA and improvements in the interaction with the physical and social environment. All these factors, together with social support, were identified as facilitators to PA one year after the PA programme.Nevertheless, body complexes caused by skin folds can be a personal barrier to PA in activities requiring revealing clothes, in which participants can feel socially exposed . In this regard, it is of utmost importance that the closest social environment of these patients  emphasizes the importance of health and quality of life over aesthetics, to favour that patients are more satisfied with their body shape. Moreover, it would be desirable to guarantee, in PA contexts, inclusive social environments in which exercisers are respectful of other people’s appearances. The physical environment should also be inclusive. Exercise facilities should possess specific designs and physical structures to preserve patients’ privacy if they have some body complex and do not want to feel observed by others .The pain associated with knee or hip osteoarthritis was another barrier to PA. Perhaps, instead of avoiding PA, bariatric patients need to know what type of exercise they should do to avoid pain, favour rehabilitation, and improve their physical functioning. The exercise counselling by qualified professionals seems necessary for bariatric patients. Coping with unfavourable weather conditions was also reported as a barrier to PA. However, the climate of Alicante (Spain) does not seem to represent an important physical environmental barrier to PA. Lack of motivation, or other passive leisure preferences, may be also influencing bariatric patients’ perception of this barrier. Another perceived barrier to be active was lack of social support. Future interventions for the promotion of PA might be also focused on patients’ relatives and friends, as a way to enhance more active and supporting social environments.The lack of economic resources and unemployment were perceived by bariatric patients as obstacles to do PA. Health education focused on healthy habits and PA promotion would be necessary so that unemployed bariatric patients find economical ways to be active. At the same time, some participants perceived the lack of time and exhaustion associated with long workdays as a difficulty to be active. In order to promote PA, employers should make efforts to avoid very long working hours and work-overload for their workers, which seems quite incompatible with an active lifestyle. Companies could also promote active recess especially in those employees who work sitting , enable space for exercise in the company facilities or near to them, or contracting a sport sciences professional who could supervise personal or group-based exercise programmes for company employees.The end of the PA programme represented one of the most important barriers for the patients to continue with an active lifestyle. It would be beneficial for public health systems to include PA programmes and advisory exercise services for these patients. This action requires building bridges of relationships between medical staff and exercise and sport sciences professionals. Moreover, it would be necessary to investigate the cost-benefit of implementing these services and explore ways to make them economically sustainable. In this regard, previous research has pointed out that the investment in the promotion of PA is necessary to reduce the economic costs of the diseases related to physical inactivity in the health systems Kruk, .


Both, arrhythmogenic right ventricular cardiomyopathy (ARVC) and regular training are associated with right ventricular (RV) remodelling. Cardiac magnetic resonance (CMR) is given an important role in the diagnosis of ARVC in current task force criteria (TFC), however, they contain no cut-off values for athletes. We aimed to confirm the added value of feature tracking and to provide new cut-off values to differentiate between ARVC and athlete’s heart. Healthy athletes with training of minimal 15 h/week (n = 34), patients with definite ARVC (n = 34) and highly trained athletes with ARVC (n = 8) were examined by CMR. Left and right ventricular volumes and masses were determined. Global right and left ventricular, and regional strain analysis for the RV free wall was performed using feature tracking on balanced steady-state free precession cine images. 94% of healthy athletes showed RV dilatation of the proposed TFC, 14.7% showed RV ejection fraction (RVEF) between 45–50%, none of them had RVEF < 45%. Although RVEF showed the highest accuracy in differentiating between athlete’s heart and ARVC, only 37.5% of athletes with ARVC showed RVEF < 45%. The only parameters falling in the pathological range  in all athletes with ARVC were the strain and strain rate of the midventricular RV free wall. Establishing RVEF and RV strain analysis provides an important tool to distinguish ARVC from athlete’s heart. CMR based regional strain and strain rate values may help to identify ARVC even in highly trained athletes with preserved RVEF. Prolonged endurance exercise may lead to pronounced morphological changes of the right ventricle . However2  or ≥ 100 ml/m2  or RV ejection fraction ≤ 40%. As a minor criterion regional RV akinesia or dyskinesia or dyssynchronous RV contraction and a ratio of RVEDVi ≥ 100 to < 110 ml/m2  or ≥ 90 to < 100 ml/m2  or RV ejection fraction > 40% to ≤ 45% is required [Overlapping electrical and structural features of athlete’s heart and ARVC—such as right bundle branch block, T-wave inversion in precordial leads, elevated RV end-diastolic volume (RVEDVi) or slightly decreased EF—may cause diagnostic difficulties. Current TFC require as a major criterion regional RV akinesia or dyskinesia or dyssynchronous RV contraction and RVEDVi ≥ 110 ml/mTissue tracking technology such as speckle tracking echocardiography and feature tracking CMR recently have become a subject of great interest for clinicians managing patients with ARVC. Feature tracking technique allows us to estimate myocardial strain, a measure of deformation using balanced steady-state free precession (bSSFP) cine images. Recent literature data imply, that CMR based deformation imaging using feature tracking technology may have an important added value in the diagnostic workup of ARVC patients –8, althoConnection between sport activity and ARVC is an intensively studied topic. It is a proven fact, that high intensity exercise is a strong independent marker of life-threatening arrhythmias  and exerOur goal was to compare conventional left and right ventricular parameters of healthy athletes with non-athletic ARVC patients, and to investigate clinical and detailed CMR characteristics of active highly trained athletes with ARVC. We tested the diagnostic accuracy of TF CMR criteria regarding RVEDVi and RVEF, and we tested whether global or regional strain analysis could improve the diagnostic value of CMR in this special patient population.This study was conducted between 2010 and 2017. ARVC patients with definite diagnosis based on the revised Task Force criteria were consecutively enrolled (n = 34). Highly trained healthy athletes with a minimum of 15 h of training per week for at least 5 years performing sports with high dynamic and static components  were recCMR examinations were conducted on a 1.5 T MR scanner  with a 5-channel cardiac coil. Locaizing scans were followed by breath-hold cine imaging in transversal planes. Retrospectively-gated, balanced steady-state free precession (bSSFP) segmented cine images were acquired in 2-chamber, 4-chamber and LV outflow tract views. Short-axis images with full coverage of the left and right ventricle, and RV outflow tract images were obtained with a temporal resolution ≤ 40 ms, with a mean echo time/repetition time/flip angle: 1.35 ms/2.7 ms/60°, respectively. 30 phases per cardiac cycle were acquired with one or two slices per 10–14 s breath-hold depending on the patients/individuals breath-hold capacity. Image domain based parallel imaging (SENSE) was used in case of short-axis movies (acceleration factor 2.0). Spatial resolution regardless of the field-of view (350 mm on average adapted to body size) with a mean acquisition pixel size of 1.6 mm × 1.6 mm, slice thickness was 8 mm with no interslice gap.Late gadolinium enhancement (LGE) imaging was performed if patients gave their informed consent . During an inspiratory breath-hold, a bolus of gadobutrol (0.15 mmol/kg) was injected at a rate of 2–3 ml/s through antecubital intravenous line. Contrast-enhanced images were acquired using a segmented inversion recovery sequence with additional phase sensitive reconstructions in long- and short-axis views  10–20 min after contrast administration. Parallel imaging is not utilized in LGE images. The inversion-time was adjusted to provide optimal suppression of apparent normal myocardium.All images were evaluated with Medis Suite (QMass and QStrain) Software . Endocardial and epicardial contour detection was performed by a blinded expert observer manually on short axis cine images in end-systolic and end-diastolic phases. Quantification of the left and right ventricular ejection fraction , end-systolic volume , end-diastolic volume , stroke volume  and myocardial mass  were performed. Left and right ventricular volumes and masses were standardized to body surface area (BSA)—LVESVi, RVESVi, LVEDVi, RVEDVi, LVSVi, RVSVi, LVMi and RVMi. Regional right ventricular akinesis, dyskinesis, dyssynchrony were qualitatively assessed. Global LV and RV strain analysis was performed based on cine images after manual contouring of the endocardial borders. Additionally, regional strain analysis for the right ventricular free wall was performed based on RV endocardial contours on 4CH-view, peak systolic longitudinal strain and strain rate values of the basal, midventricular and apical free wall were established. Average and minimal values of the measured regional strain and strain rate values were also determined.t test, or Mann–Whitney U-test where appropriate. Diagnostic accuracy of CMR parameters was evaluated using receiver operating characteristic (ROC) curve analysis with ≥ 4 Task Force Score . For area under the curve (AUC), a value of 0.9–1.0 was considered excellent, 0.75–0.9 good, 0.6–0.75 moderate and 0.5–0.6 poor. Optimal cut-off values for ARVC patient vs. athlete classification were derived from ROC curves coordinates by maximizing the proportion of subjects correctly classified. A p-value of ≤ 0.05 was considered statistically significant. Statistical analysis was performed with MedCalc software (version 17.9).Continuous variables were reported as mean and standard deviation, and categorical variables as frequency and percentages. Between-group comparisons were performed with the unpaired Student’s 2 in males, > 100 ml/m2 in females) in all healthy male athletes and 83.3% of healthy female athletes. RVEDVi of the remaining female athletes were in the proposed range of the minor TFC . None of the athletes showed RVEF ≤ 45%, RVEF between 45 and 50% was observed in 5 cases .Thirty-four highly trained healthy athletes with no signs of cardiovascular disease and with a minimum of 15 h of training per week for at least 5 years performing sports with high dynamic and static components  were recruited, including canoe and kayakers (n = 17), rowers (n = 5), boxers (n = 5), triathletes (n = 4) and cyclists (n = 3). None of the healthy athletes had positive family history of sudden cardiac death or ARVC, all of them were asymptomatic. None of the healthy athletes had any ECG abnormality suggesting structural heart disease, none of them showed T-wave inversion in more than 1 continuous leads, Q wave inversion or ST-depression. 81% of athletes showed J-point elevation, 19% Sokolow or Cornell index positivity for left ventricular hypertrophy. None of them showed regional right ventricular wall motion abnormality or late gadolinium enhancement (LGE). RVEDVi was in the proposed range of the major TFC , but only blunted deconditioning effect was observed on RV values, RVEDVi remained in the pathological range (169.7 ± 10.5 ml/m2 vs. 137.3 ± 17.1 ml/m2). Four athletes had documented sustained VT or VF, and aborted sudden cardiac death was reported in two cases. None of them had positive family history for ARVC or SCD. Two athletes did not fulfil any repolarization or depolarization criteria, TWI in lead v1–v2 and in v1–v3 leads was observed in one and four athletes, respectively. One patient had complete right bundle branch block. Epsilon wave was observed in 3 patients. Average Task Force score was 5.4 points  the comprehensive investigation including resting ECG, ambulatory ECG monitoring, echocardiography, CMR and patient history confirmed the diagnosis  was decreased in the ARVC group compared to athletes. Regional longitudinal strain and strain rates of the RV free wall are presented in Table Establishing AUC values for the CMR parameters RVEF showed good accuracy (AUC = 0.830), whereas RVEDVi failed as a discriminator between ARVC and athlete’s heart (AUC = 0.599). Cut-off value for RVEF ≤ 45.8 discriminates between ARVC and athlete’s heart with a sensitivity of 68% and a specificity of 100%. RV mid strain, average and minimum of the measured regional strain values demonstrated good discrimination between athlete’s heart and ARVC. We investigated whether establishing gender-specific cut-off values may influence the diagnostic accuracy, but comparing male and female ROC curves for CMR parameters with the highest diagnostic accuracy  showed no significant difference. These results suggests that gender-specific differences regarding these parameters are negligible, so we present cut-off values for both males and females. Cut-off values for global and regional strain values are presented in Table We tested the established cut-off values for CMR parameters in the group of highly trained athletes with diagnosed ARVC. Applying the established cut-off values, RVEF was in the pathological range in only 3 athletes with ARVC. Half of the athletes with ARVC showed normal RV GLS. Regional longitudinal strain and strain rate of the RV mid free wall were in the pathological range among all 8 athletes with ARVC  and 1–2 × 1–2 mm in plane resolution with a slice thickness of 6–8 mm . TechnicAlthough several echocardiographic studies have investigated the morphologic right ventricular adaptation of elite athletes , limitedBecause of the pronounced RV adaptation observed in healthy highly trained athletes, diagnosing ARVC in elite athletes is more challenging than in sedentary individuals. Our findings imply that the phenotype of sedentary and athletic ARVC patients differ. We are the first to report detailed functional and morphological characteristics, and CMR based strain values of an athlete cohort with definite ARVC in training or competition period. According to literature data ejection fraction may stay in normal range especially in athletes with structural heart disease, but literature data imply that decreased strain values could indicate decreased function earlier than ejection fraction . Based oRegional strain and strain rate of the right ventricular mid free wall are valuable discriminators even in patients with preserved RVEF and normal RV GLS. This fact highlights the significance of reporting CMR based strain parameters for differentiating athlete’s heart and ARVC. Due to the moderate sensitivity our cut-off values confirms that CMR is not an appropriate first line screening method, good or excellent specificity enhances its role to prevent unnecessary disqualification because of overdiagnosing ARVC.The major limitation of our study is the single-center nature and the limited number of participants. Additionally, our ARVC patients represent an older population compared to our athletes, although age differences may not necessarily influence our results—there have been contradictory data originating from the studies on the effect of aging on strain values , 28. AnoOur study highlights that RV dilatation in healthy endurance athletes with regular and intensive training may reach the proposed Task Force criteria in almost 95%. Therefore, elevated RVEDVi is an insufficient criterion for morphological diagnosis of ARVC. Besides establishing RVEF using CMR, RV strain analysis can provide an important tool to diagnose ARVC and distinguish it from athlete’s heart. CMR based regional strain and strain rate values may help to identify ARVC even in highly trained athletes with preserved RVEF and normal RV GLS.


Interventional ablation has been demonstrated to represent an effective therapy in patients with atrial fibrillation (AF), leading to restoration and maintenance of sinus rhythm in the majority of cases. However, recurrence of AF is encountered in 35% to 40% of cases, and the causes for this frequent complication have not been elucidated so far.Here we present the study protocol of the FIBRO-RISK trial, a prospective, single-center, cohort study which aims to investigate the impact of inflammatory-mediated myocardial fibrosis on the risk of recurrence after successful catheter ablation of atrial fibrillation. The level of systemic inflammation in the pre-ablation and immediate post-ablation period will be assessed on the basis of serum levels of inflammatory biomarkers , while the level of cardiac fibrosis will be determined based on cardiac magnetic resonance imaging associated with complex post-processing techniques for mapping myocardial fibrosis at the level of left atrium and left ventricle. At the same time, the amount of epicardial fat will serve as an indirect marker of localized inflammation and will be determined at different levels in the heart , while ventricular function will be assessed on the basis of serum levels of NT-proBNP prior to the procedure. All these parameters will be investigated in patients with successful ablation of AF, who will be divided into 2 groups: group 1 – patients who develop AF recurrence at 1-year, and group 2 – patients with no recurrence of AF at 1-year. In all patients, the following biomarkers will be determined: serum levels of inflammatory biomarkers and NT-proBNP at 24 hours and 1-year post procedure, the amount of myocardial fibrosis at the level of left atrium and left ventricle at baseline +/− 7 days, and the amount of epicardial fat surrounding left atrium, right atrium and the entire heart at baseline +/− 7 days.The primary endpoint of the study will be represented by the rate of AF recurrence at 1-year post ablation, documented by either ECG or Holter monitoring. The secondary endpoints of the study will consist in:1.the rate of re-hospitalization,2.the rate of survival without relapse, and3.the rate of major adverse cardiovascular events .In conclusion, FIBRO-RISK will be the first CMR-based study that will investigate the impact of inflammation-mediated myocardial fibrosis and ventricular remodeling on the risk of recurrence after successful ablation of AF, aiming to validate inflammatory biomarkers and myocardial fibrosis as predictors for AF recurrence. Several risk factors for the occurrence and recurrence of AF have been described in the literature, including left atrial (LA) enlargement, left ventricular (LV) dysfunction, the amount of epicardial fat surrounding cardiac structures, or myocardial fibrosis. However, the relationship between inflammatory-mediated myocardial fibrosis and AF recurrence after radiofrequency catheter ablation has not been elucidated so far.Atrial fibrillation (AF) has an increasing prevalence, being currently the most frequent type of supraventricular arrhythmia and representing a significant burden for the healthcare system. In most of the cases, myocardial tissue located at the level of the pulmonary veins represents the origin of AF. The pathophysiology of AF is still incompletely understood, several studies suggesting that profibrotic and inflammatory processes can play a crucial role in the development of AF.Here we present the study protocol of the FIBRO-RISK trial, a prospective, single-center, cohort study which aims to investigate the impact of inflammatory-mediated myocardial fibrosis on the risk of recurrence after successful catheter ablation of AF.1.2primary objective of the study is to investigate the correlation between the degree of LA and LV fibrosis quantified by cardiac magnetic resonance (CMR), inflammatory biomarkers, and the risk of AF recurrence post catheter ablation.The secondary objective of the study is to investigate the correlation between structural remodeling of the left and right atrium, epicardial fat tissue volume and serum inflammatory biomarkers in patients with AF undergoing successful catheter ablation and their impact on long term outcomes.The 22.1This is a clinical prospective, non-randomized, cohort, single-center study to investigate the relationship between inflammatory status, inflammation-mediated atrial and ventricular fibrosis and remodeling, and the risk of AF recurrence. The duration of the study is 2 years which include the initial screening and the follow-up period for the recurrence of AF.2.2Declaration of Helsinki of 1975, and all patients will sign an informed consent and will be checked for the inclusion and exclusion criteria prior to enrollment in the study.The study protocol was approved by the Ethics Committee for Scientific Research of the University of Medicine and Pharmacy of Tirgu Mures  and the Ethics Committee for Scientific Research of the Cardio Med Medical Center . All study procedures comply with the 2.3The study will include 100 subjects with AF suitable for catheter ablation. Imaging biomarkers and laboratory analyses such as: high sensitive C Reactive Protein (hsCRP), matrix metalloproteases (MMPs), interleukin-6 (IL6) and N-Terminal Pro–B-Type Natriuretic Peptide (NT pro-BNP) will be determined in the first 24 hours after the procedure. The anatomy of pulmonary veins, atrial fibrosis, atrial volumes and the amount of epicardial fat will be evaluated and quantified with late gadolinium-enhancement cardiac magnetic resonance (LGE-CMR). All these parameters will be investigated in patients with successful ablation of AF, who will be divided into 2 groups: group 1 – patients who develop AF recurrence at 1 year, and group 2 – patients with no recurrence of AF at 1 year. In all patients, the following biomarkers will be determined: serum levels of inflammatory biomarkers and NT-proBNP at 24 hours and 1-year post procedure, the amount of myocardial fibrosis at the level of left atrium and left ventricle at baseline +/− 7 days, and the amount of epicardial fat surrounding left atrium, right atrium and the entire heart at baseline +/− 7 days.The study will be conducted over a period of 2 years, in which patients will be examined at baseline, and will be followed-up for recurrence of AF, as shown by the FIBRO-RISK diagram with the flowchart that will be used in the study Fig. .Inclusion criteria:Patients with non-valvular paroxysmal or persistent AF who undergo successful catheter ablation, either by cryoablation or by radiofrequency advanced 3D mapping system;Ability to provide informed consent;Patients aged at least 18 years;Exclusion criteria:Patients with valvular AF;Patients with acute coronary syndrome in the last 30 days;Patients in whom AF is presumed to be caused by hyperthyreosis;Patients with long-standing persistent or permanent AF;Unwillingness or incapacity to provide informed consent;Allergy to gadolinium contrast media;Absolute or relative contraindications to magnetic resonance imaging;Pregnancy or lactation;Women with childbearing potential in absence of any contraceptive treatment;Renal insufficiency (creatinine greater than 1.5 mg/dL) or renal failure requiring dialysis;Active malignancy or malignancy within the last 5 year prior to enrollment;Conditions associated with an estimated life expectancy of under 2 years;2.4The study will be conducted in the Center of Advanced Research in Multimodality Cardiac Imaging of the Cardio Med Medical Center, and is funded by the Romanian Ministry of European Funds, the Romanian Government and the European Union, as part of the research grant number 103545/2016 – CardioIMAGE (contract 43/05.09.2016), which was selected for funding following an international peer-review procedure within the national competition of research grants.2.5One hundred patients with successful ablation of AF who meet the selection criteria will be divided into 2 groups, namely subjects who develop AF recurrence at 1-year post ablation (group 1) and subjects with no recurrence of AF at 1-year post ablation (group 2).2.6The following information will be collected from all patients: baseline demographics, history and physical examination findings, cardiovascular risk factors. Conventional 12-lead EGC was performed in each patient at baseline, 1, 3, 6, 12 months follow-up visit.2.6.1Complete blood count and biochemistry will be evaluated at the central laboratory of the County Clinical Emergency Hospital of Tirgu Mures as per routine clinical practice, at baseline.Inflammatory status will be assessed at baseline, respectively at 1-year post procedure. hsCRP levels will be assayed by immunoturbidimetric assay . Matrix metalloprotease 9 and interleukin-6 levels will be assessed via enzyme immunoassay (ELISA) method . Determination of all inflammatory biomarkers will be performed at the Advanced Medical and Pharmaceutical Research Center of the University of Medicine and Pharmacy Targu-Mures. NT-proBNP serum levels will be determined prior to the procedure, at 24 hours, and repeated after 1 year, at the central laboratory of the Emergency Clinical County Hospital of Tirgu-Mures using an electrochemiluminescent immunoassay .2.6.2All patients will undergo transthoracic echocardiography with simultaneous ECG recording at baseline and 1-year post ablation procedure. Echocardiographic assessment will be performed with a Vivid E9 echocardiographic equipment , at rest, in the lateral decubitus position. Standard M-mode, 2-dimensional and Doppler images will be acquired as per American Society of Echocardiography standards. Left ventricular volumes and ejection fraction will be quantified and calculated according to Simpson rule, using images acquired in the apical 4-chamber plane. All measurements will be averaged for at least 3 heart cycles.2.6.3All CMR examinations will be performed with an 1.5 T Siemens Magnetom Aera magnetic resonance equipment . LV function will be assessed using cine sequences in long-axis (2-chamber and 4-chamber) and short axis. Short-axis volumetry will be used for determination of LV mass, LV ejection fraction, LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV). Ventricular and atrial fibrosis will be assessed using late postgadolinium myocardial enhancement sequences (LGE) at 10 minutes after intravenous injection of gadolinium extracellular contrast agents. Acquired LGE images will be post-processed using the Medis QMass 8.1 software  with definition of the epicardial and endocardial contours and manual setting of the hyper-enhancement threshold for the recorded sequence of slices. Delayed signal intensity (DSI) analysis performed in 10 to 12 consecutive short-axis LGE images. The full width at half maximum will be used for image segmentation, using an automated hyper-enhancement threshold and fibrotic areas will be considered those with slow washout kinetic.Quantification of epicardial fat volume will be performed by tracing and manually adjusting epicardial contours, as part of the post-processing protocols.2.6.4Seldinger technique will be used for venous access, with 1 sheath positioned on the left and 2 sheaths on the right femoral veins. A decapolar diagnostic catheter will be placed in the coronary sinus, after being advanced via left femoral access site and secured with a 6F sheath.Transesophageal echocardiography will be used to guide interatrial septal puncture. A bolus of 5000 to 7500 U of heparin followed by 1000 to 2000 U/h will be administrated and the following heparin dosage will be adjusted using activated clotting time, determined every 15 to 30 minutes.TM NavXTM system, Model EE3000 , improved by fusing images acquired with CMR images. After inserting the mapping catheter in the ostium of the pulmonary vein (PV), radiofrequency catheter ablation will be performed to obtain pulmonary vein isolation. Ablation will consist in applying a 30 W energy and a 10 to 30 g pressure with temperature adjusted at 50°C, by an irrigated (5–20 ml/min) contact force-sensing catheter positioned on the left atrial wall. A PV will be considered electrically isolated by eliminating all electrical potentials, or by demonstrating successful PV potential dissociation.In case of radiofrequency ablation, 1 non-steerable sheath will be used for placing the duodecapolar mapping catheter (Lasso) and the other steerable sheath for placing the 3.5 mm tip externally irrigated contact force-sensing ablation catheter. A continuous heparinized saline wash of the long sheaths will be provided during the entire procedure. The 3-D electro-anatomical map will be acquired with the EnSiteIn case of cryoablation procedure, a cryoablation balloon  will be advanced with transesophageal control via transseptal route and will be placed at the ostium of each pulmonary vein, delivering minus 40 to 70° cooling energy, during 180 to 240 seconds application. The ablation will be considered efficient when complete electrical block between atrial tissue and pulmonary vein will be achieved.2.7The clinical trial will be conducted from January 2019 to December 2020.2.8primary outcome of the study is represented by the rate of AF recurrence at 1-year post ablation, documented by either ECG or Holter monitoring.The Secondary outcome refers to rate of re-hospitalization, rate of survival without relapse and rate of major adverse cardiovascular events 2.9Baseline (day 0)oObtain and document consent from participant on study consent form.oVerify inclusion/exclusion criteria.oObtain demographic information, medical history, medication history, alcohol and tobacco use history.oRecord results of physical examinations and 12-lead ECG.oCollect blood specimens .oImaging procedures: transthoracic 2-D echocardiography, late gadolinium-enhancement CMRoCatheter ablation (radiofrequency or cryoablation)Follow-up visits oRecord results of physical examinations, 12-lead ECG and medical history.oImaging procedures: transthoracic 2-D echocardiographyFinal study visit (month 12)oRecord results of physical examinations, medical history,12-lead ECG and determination of serum levels of inflammatory biomarkers and NT-proBNPoImaging procedures: transthoracic 2-D echocardiographyoEnd-point evaluation.2.10Medical history, clinical examination, laboratory tests ;12-lead ECG2D transthoracic echocardiography with measurement of: cardiac diameters, volumes, valvular function and regurgitation, pressure gradients, left ventricular systolic and diastolic function and ejection fraction.Late Gadolinium-Enhancement CMR with the evaluation of: left and right atrial volume, volume of epicardial adipose tissue, degree of atrial and ventricular fibrosisPulmonary vein isolation radiofrequency ablation with advanced 3D mapping system or cryoablation.2.11All the information will be collected in a database that consists of patient's background, medical history, medication, imaging features provided by cardiac ultrasound, CMR and imaging post-processing.2.12The study will include 100 subjects with AF undergoing successful ablation of pulmonary veins via interventional route. After analysis of follow-up data, patients will be distributed in two groups according to the presence or absence of recurrent episodes of AF during the follow-up.Sample size calculation was performed using the StatMate 2.0 software. For sample calculation, the proportion of event-free population was estimated at 60%. According to this calculation, a sample size of 50 patients in each subgroup has a 90% power to detect an increase in MACE-free rates proportion of 0.29, with a significance level  of 0.05 (2-tailed). Therefore, the total sample size was established at 100 patients.2.13t test. Non-normally distributed variables will be analyzed using the Mann-Whitney test. Categorical variables will be expressed in numbers and percentages and will be compared using the Fisher exact test.Statistical analysis will be performed using Graph Pad InStat 3.10 software at the level of significance 5%. All data will be checked for normality. Continuous variables with normal distribution will be presented as mean ± standard deviation and will be compared using 3This study presets the protocol of a prospective, single-center, cohort study which aims to investigate the impact of inflammatory-mediated myocardial fibrosis on the risk of recurrence after successful catheter ablation of AF.,4 In the latest years, a large number of studies tried to identify predictors for a successful outcome on long term after AF ablation, however reliable clinical markers to predict sinus rhythm maintenance or AF recurrence have not been identified so far. The main contribution of the present study will be to validate new clinical features, such as inflammatory biomarkers, epicardial fat, ventricular remodeling or myocardial fibrosis, as predictors of AF recurrence in patients who are scheduled for catheter ablation. In this trial we hypothesize that several imaging markers associated with cardiac structural alteration, provided by CMR , associated with serum inflammatory biomarkers  could form a powerful prediction panel to predict the risk of AF recurrence in the post ablation period, reflecting the impact of inflammatory-mediated myocardial fibrosis on the risk of arrhythmia.Although AF ablation procedures are constantly improving, recurrences continue to be problematic as a significant proportion of patients present with AF relapse despite an optimum management in the post-ablation period. It is well known that a higher amount of atrial fibrotic tissue can favor atrial arrhythmogenesis.,6 At the same time, the amount of contrast enhancement in the LA wall, considered to represent the volume of fibrotic tissue of the total LA wall, has been recently described by prospective trials to be independently associated with the likelihood of recurrent arrhythmia after ablation.,6,7 Previous studies showed that pre-existing fibrosis on LGE-CMR was the strongest independent predictor of ablation procedure failure and arrhythmia recurrence. McGann et al proved that subjects with >30% atrial fibrosis on LGE images at baseline had a 71% chance of AF recurrence at 1 year.The relationship between inflammation, myocardial injury and atrial fibrillation has been extensively studied in the recent years. Several recent studies managed to assess the feasibility of LGE-MRI in detecting both pre-existing and post-ablation atrial and ventricular fibrosis.,11–14 Their results raised interest in the use of CMR as a periprocedural risk assessment tool. Despite these promising results, the assessment of atrial and ventricular fibrosis has not yet been widely adopted in clinical practice.–18 We should not forget that the capacity of LGE-CMR to detect fibrosis in the atria is still controversial due to the lack of reproducibility. Thus, this trial aims to validate myocardial fibrosis, targeting both atrial and ventricular fibrosis quantified by CMR, as predictor for AF recurrence.Beside baseline evaluation, several studies suggest that quantification of post ablation LA scarring may play a role in determination of the AF recurrence risk.,19–22 Therefore, the role of inflammation in AF recurrence has been recently proposed as a new and challenging hypothesis to explain the high rate of recurrence after AF conversion.,21,23–26 As the exact pathways from inflammation to AF are still unclear, it is presumed that inflammatory cytokines may bind to atrial myocytes inducing tissue damage. In line with this hypothesis, the FIBRO-RISK trial aims to investigate the correlation between inflammatory biomarkers and cardiac fibrosis, evaluated via LGE-CMR, in order to prove the impact of inflammatory-related myocardial fibrosis on the risk of recurrence after successful catheter ablation of AF.Previous observational studies showed that elevation of several inflammatory serum biomarkers, such as hsCRP or IL-6, are associated with occurrence and recurrence of AF, since patients with AF present significantly higher levels of inflammatory biomarkers as compared with subjects maintaining sinus rhythm.,21,23–26 A very recent study demonstrated that in patients admitted in an intensive care facility, the presence of ventricular remodeling leading to ventricular dysfunction was associated with a higher incidence of AF and conduction abnormalities. NT-proBNP is a biomarker reflecting ventricular dysfunction, which has been shown to predict AF recurrence unrelated to ablation procedure.,29 However, it still remains unclear if these biomarkers are useful predictors of AF recurrence after ablation. In the FIBRO-RISK study, we aim to validate, for the first time in the literature, the role of ventricular remodeling, serum biomarkers associated with ventricular dysfunction, inflammation and myocardial fibrosis, assessed by LGE-CMR, as independent predictors of AF recurrence after successful catheter ablation, in order to prove that inflammation can play a significant role in the complex interrelation between myocardial dysfunction, remodeling and AF recurrence.Besides inflammation, neurohormonal activation, classically associated with ventricular dysfunction, has been shown to play a significant role in the recurrence of AF following pulmonary vein isolation.4FIBRO-RISK will be the first CMR-based study that will investigate the impact of inflammation-mediated myocardial fibrosis on the risk of recurrence after successful catheter ablation of AF, aiming to validate inflammatory biomarkers and myocardial fibrosis as predictors for AF recurrence.Submission to ethical committee was performed by Korodi Szilamer. The radiologist responsible for CMR imaging interpretation is Mihaela Ratiu. Korodi Szilamer, Roxana Hodas and Theodora Benedek will perform data statistical analysis. All the authors approved the final manuscript.Conceptualization: Szilamer Korodi, Rodica Toganel, Roxana Hodas, Mihaela Ratiu, Andras Mester, Istvan Kovacs, Imre Benedek.Data curation: Theodora Benedek, Kovacs Istvan.Formal analysis: Andras Mester, Theodora Benedek.Investigation: Mihaela Ratiu, Theodora Benedek, Istvan Kovacs.Methodology: Szilamer Korodi, Rodica Toganel, Imre Benedek, Theodora Benedek.Resources: Imre Benedek.Supervision: Imre Benedek, Theodora Benedek.Validation: Mihaela Ratiu.Visualization: Mihaela Ratiu, Andras Mester.Writing – original draft: Szilamer Korodi, Rodica Toganel, Roxana Hodas, Mihaela Ratiu, Andras Mester, Istvan Kovacs, Imre Benedek.Rodica Toganel orcid: 0000-0001-6510-9646.


Determine the prognostic impact of scar quantification (scar %) by cardiac magnetic resonance (CMR) in predicting heart failure admission, death and left ventricular (LV) function improvement following cardiac resynchronisation therapy (CRT), after controlling for the presence of left bundle branch block (LBBB), QRS duration (QRSd) and LV lead tip location and polarity.Consecutive patients who underwent CMR between 2002 and 2014 followed by CRT were included. The primary endpoint was death or heart failure admission. The secondary endpoint was change in ejection fraction (EF) ≥3 months after CRT. Cox proportional hazards, linear regression models and change in the area under the receiver operating characteristic curve (AUC) were used.A total of 84 patients were included . After adjusting for clinical factors, presence of LBBB and QRSd and LV lead tip location and polarity, greater scar % remained associated with a higher risk for clinical events  and a smaller improvement in EF . When adding scar % to QRSd and LBBB, there was significant improvement in predicting clinical events at 3 years  and EF increase ≥10% .Scar quantification by CMR has an incremental value in predicting response to CRT, in terms of heart failure admission, death and EF improvement, independent of the presence of LBBB, QRSd, LV lead tip location and polarity. Approximately one-third of patients who receive cardiac resynchronisation therapy (CRT) do not benefit and better identification of patients who will respond is crucial. Scar quantification by cardiac magnetic resonance (CMR) has been postulated to predict clinical response to CRT; however, its independent and incremental value to currently adopted selection criteria (presence of left bundle branch block and QRS complex duration), and when taking into account left ventricular (LV) lead characteristics and the type of cardiomyopathy, has not been evaluated.Scar quantification by CMR appears to independently predict clinical events and LV functional improvement, in both ischaemic and non-ischaemic cardiomyopathy, even when accounting for clinical, electrocardiographic and LV lead characteristics. It adds incremental value to currently adopted selection criteria for the prediction of CRT response.Scar quantification by CMR prior to CRT implantation may allow better identification of patients who would respond to this therapy.Cardiac resynchronisation therapy (CRT) is an established therapeutic option for select heart failure patients with reduced ejection fraction (EF) and ECG evidence of dyssynchrony.We sought to assess whether scar quantification by CMR is independently and incrementally predictive heart failure hospitalisation and death after CRT implantation when accounting for clinical data, the presence of LBBB and QRSd, and LV lead tip position in relation to scar20 21All consecutive patients who underwent CMR testing at our institution  between January 2002 and June 2014, and had subsequent CRT implantation were initially included. Patients who underwent CRT-P (CRT-Pacemaker) without defibrillator (CRT-D) and those with significant time delay between the CMR scan and CRT implantation (more than 1-year for ischaemic cardiomyopathy (ICM) and more than 2 years for non-ischaemic cardiomyopathy (NICM)) were excluded. Baseline clinical characteristics were determined by chart review. Ischaemic cardiomyopathy was defined as presence of severe coronary disease on cardiac catheterisation, prior coronary revascularisation (coronary bypass surgery or percutaneous intervention) and by its characteristic scar pattern on CMR.22The CMR scan was performed an average of 87 days before CRT implantation. All studies were obtained on dedicated CMR scanners . For assessment of global cardiac function, steady-state free precession short axis LV stack slices were acquired . Delayed hyperenhancement (DHE) images were obtained 10 min after intravenous injection of 0.2 mmol/kg of Gadolinium meglumine (Dotarem). Scar was considered present if seen on two orthogonal views. The short axis DHE images were then analysed using commercially available software . Endocardial and epicardial borders were manually delineated. Scar was then defined using a threshold of >2 SD compared with user-defined viable myocardium for ICM and >6 SD for NICM, as these thresholds have been shown to correlate most accurately with histological fibrosis.In order to explore whether regional variations in scar % had an impact on CRT response, we divided the myocardium into four walls  comprised of the following American Heart Association (AHA) segments: septum , anterior , inferior  and lateral .The LV lead tip location was determined using post-CRT implantation postero-anterior and lateral chest radiographs.Response to CRT was assessed both clinically and echocardiographically.The primary endpoint was defined as time from CRT to death or heart failure admission. Events were determined from medical records by two independent reviewers (SCH and ST) and the first event was included in the analysis. The final censor date was 14 October 2017. The mean follow-up duration was 3.7 years.Transthoracic echocardiography (TTE) was performed on all patients prior to CRT implantation (on average 50 days prior). The EF was measured by biplane method of disks (modified Simpson’s rule) or estimated visually, in case the former was technically challenging. To assess response to CRT, we measured the EF on a TTE performed ≥90 days after CRT implantation  to allow sufficient time for the therapy to have effect. ‘Responders’ were defined as those whose EF increased by at least 10% after CRT, as lower thresholds of change in EF by the biplane method can be related to test–retest variability.26 27A Cox proportional hazards model was used for the composite clinical endpoint and a linear regression model was used for the EF endpoint. Total scar % was included as the primary predictor of interest. The following variables were added as covariates: clinical—age, gender, diabetes mellitus and hypertension; electrocardiographic—LBBB and QRSd (in ms); and LV lead characteristics—lead tip location  and polarity (unipolar vs multipolar). In order to assess whether the impact of scar on patient outcome is different for ICM and NICM patients, an interaction term was added.To be useful clinically, scar quantification by CMR needs to be not only of independent value but also of incremental value to currently adopted CRT selection criteria (presence of LBBB and QRS width). For this purpose, the incremental improvement in overall predictive accuracy due to scar was assessed by the change in the area under the receiver operating characteristic (ROC) curve. Clinical events were determined at both 1 and 3 years in accordance to published clinical trial data.A total of 111 patients were initially included. Patients receiving CRT-P (n=4), ICM patients who received CRT more than 1 year after CMR (n=16), and NICM patients who received CRT more than 2 years after CMR (n=7) were all excluded. The final sample consisted of 84 patients: 43 ICM and 41 NICM. The lead tip location and type were available in 67 patients. The LV lead tip was located in the lateral wall in 32 (48%) patients and in the inferior wall in 33 (49%) patients. Two patients had the LV lead tip in the anterior wall. In relation to regional scar by MRI, 43 patients had their lead tip in scarred myocardium and 24 had their lead tip in normal myocardium. The lead was multipolar in 44 (66%) cases (bipolar in 34 and quadripolar in 10) and unipolar in 23 (34%) cases.A total of 29 patients experienced an adverse event during follow-up (heart failure in 19 and death in 10). Total scar % was significantly higher in patients who had an event compared with those who were event free for the primary endpoint . After adjusting for the presence of LBBB and QRSd, clinical, and LV lead characteristics, older age and greater levels of scar were associated with a higher risk of the composite clinical endpoint . On the other hand, the presence of LBBB was associated with a lower risk of clinical events after CRT . Figure To address the effect of scar % on LV function, a secondary substudy analysis was performed on the patients who had TTE ≥3 months post CRT. This was available for review in 57 patients. LV EF increased by an average of 10% after CRT (range: −18% to 35%). Echocardiographic response was defined as an increase by ≥10% in EF, ≥3 months after CRT implantation.Overall, 30 patients (53%) showed significant EF improvement , while 27 (42%) did not. Over a follow-up time of 3 years, 21 patients experienced a primary event (heart failure in 13 and death in five). When responders were defined as those who were event-free 3 years after CRT, a scar threshold of 0% (absence of scar) had a specificity of 83% with a sensitivity of 40%, while a scar threshold of 33% had a sensitivity of 93%, with a specificity of 56%. 10.1136/openhrt-2019-001067.supp1Supplementary dataSimilarly, for the identification of echocardiographic CRT responders (EF increase by ≥10%), we found that a scar threshold of 0% provides a specificity of 81% with a sensitivity of 43%, while a scar threshold of 33% provides a sensitivity of 97% with a specificity of 26%. While several previous studies have demonstrated the independent prognostic ability for scar % by MRI to predict clinical response to CRT,Lack of CRT response portends a very poor survival, with mortality up to 50% at 4 years.Furthermore, a subset of patients may experience worsening LV function after CRT, suggesting that CRT can result in increased harm in select patients.In addition to clinical data and ECG markers of dyssynchrony, our findings demonstrate that scar burden remained an independent marker of worse outcomes based on highly relevant endpoints: death or heart failure and EF improvement. Moreover, our study is the first MRI study to demonstrate the incremental value when added to current CRT clinical selection criteria (presence of LBBB and QRSd).There are limitations to consider when interpreting the results of this study. This is an observational, single centre, retrospective study with all the inherent limitations. While we attempted to control for potential confounders, residual confounding cannot be excluded. Also, among patients included, 27 patients did not have an echocardiogram available for review 3 months post-CRT implant, and 26 patients were lost to follow-up before 3 years have passed, which could have biassed our results for these endpoints. Finally, lead characteristics were not available in 17 patients.Better identification of patients who would respond to CRT therapy is an important challenge. Scar quantification by CMR appears to independently predict clinical events and LV functional improvement, in both ischaemic and non-ischaemic cardiomyopathy, even when accounting for clinical, electrocardiographic and LV lead characteristics. In addition, scar burden adds incremental value to currently adopted selection criteria for the prediction of CRT response.


Heart failure is a multifaceted syndrome addressing for a high rate of death among the general population. The common approach to this disease has been always based on the evaluation of the left ventricular ejection fraction by two-dimensional echocardiography with Simpson’s method. Mounting evidences have demonstrated the pitfalls of this method and have suggested that the management of heart failure requires a deep knowledge of the pathophysiological insights of the disease and cannot rely only on the evaluation of the left ventricular ejection fraction. Several advanced imaging technologies overwhelm the evaluation of ejection fraction and could provide a better understanding of the myocardial abnormalities underlying heart failure. Considering the limitation of left ventricular ejection fraction and the systemic involvement of heart failure, classifications of heart failure based on ejection fraction should be substituted with a comprehensive “staging” of multiorgan damage, not only considering the heart but also the lungs, kidneys, and liver, such as the HLM staging system. Such a holistic approach based on the HLM staging system and multimodality imaging can provide a global assessment of patient features allowing for targeted therapies and better heart failure management. Heart failure (HF) is a complex clinical syndrome related to a wide spectrum of left ventricular function abnormalities. Nowadays, HF is one of the most common causes of hospitalization and death with great impact on social and economic resources . During Starting from the assumption of HF as a mechanical dysfunction of the heart, the measure of left ventricular (LV) function as the fraction of the LV end-diastolic volume ejected per beat was considered the best parameter for the detection and management of heart abnormalities. Firstly, Folse and Braunwald used a radioisotope indicator dilution technique  to estimIn 2012, the European Society of Cardiology HF guidelines  proposedAlthough LVEF calculated through two-dimensional echocardiography is the mainstay for the evaluation of LV function and is used to classify HF patients, it has some important limitations such as limited test-retest reliability due to inter- and intraobserver variability, preload and afterload dependence that leads to loss of reproducibility, and poor image quality, resulting in foreshortened ventricles , 7. MoreBeyond the abovementioned limitations of LVEF, the ESC classification for HF has raised some criticisms because it considered a speculative distinction not helpful for daily clinical practice. A classification should provide detailed characterization of a patient and prognostic discrimination and should allow for therapies targeted on each patient’s phenotype. Furthermore, classifying should imply mechanistic insights, grouping patients based on critical pathophysiological abnormalities .Conversely, LVEF is not related to any specific clinical feature or mechanistic insights; thus, LVEF-based HF classification may result inappropriate in providing pathophysiological distinctions. In fact, patients with HFpEF often have subclinical systolic impairment detected by speckle tracking echocardiography as reduction of global longitudinal strain (GLS) , whereasAdditionally, the introduction of a third distinct group of patients with an LVEF of 40 to 49%, the HFmrEF group, seems to be inappropriate and results in misleading and confusing findings. This group does not really exist in daily practice as a distinct class of HF patients because it has no distinguishable features and appears to be a transitory phase between two extremities of the wide spectrum of HF manifestations . Though Lastly, although a good predictor of cardiac events when LVEF is below 45%, the LVEF-based HF classification has shown a limited prognostic value in predicting the risk of all-cause morbidity and mortality in patients with EF > 45% , thus reOverall, several pitfalls reduce the reliability of LVEF measured through two-dimensional echocardiography and make the LVEF-based classification of HF less useful for patients and clinicians. The aforementioned limitations of the ESC classification system warrant the use of a more comprehensive assessment of HF and LV function, beyond the LVEF, using advanced imaging technologies such as three-dimensional echocardiography, longitudinal strain by speckle tracking echocardiography, and cardiovascular magnetic resonance (CMR) with evaluation of late gadolinium enhancement (LGE). These techniques could allow better definition of pathophysiology, management, and prognosis of HF rather than LVEF alone.2), and (c) diastolic dysfunction. In 2012, the European Society of Cardiology HF guidelines [From the 1990s, HF patients began to be selected based on LVEF. “HFpEF” replaced the old “diastolic” heart failure, and HFrEF replaced the old “systolic” heart failure because diastolic dysfunction of the left ventricle may also characterize HFrEF  and subtidelines  proposedidelines . In 2016idelines . In the idelines  defined idelines  defined idelines : “Cardioidelines  defined idelines  proposedidelines . The MOGFurther genetic research and development of multicenter registries are needed to clarify the clinical advantages and to make MOGE(S) classification of CMP more practical.Left ventricle global function is usually assessed by LVEF expressed as a percent value and calculated from estimations of LV volumes. The ideal imaging technique to assess LV cardiac function would be widely available, cheap, fast, with no need of ionizing radiation or contrast administration, and able to provide accurate and reproducible measurements. There is no imaging test meeting all of these characteristics. Echocardiography has some advantages as it is non-invasive, widely available, portable and relatively inexpensive. The biplane method of disks (modified Simpson’s rule) is the currently recommended two-dimensional (2DE) method ; howeverThree-dimensional echocardiography (3DE) provides volumes with minimal post-processing and overcomes some of the 2DE limitations such as the geometrical assumption. 3DE-based LVEF measurements are more accurate and reproducible with the closest approximation to CMR-derived measurements –33, and Independent of the technology used, LVEF has intrinsic limitations: LVEF is not an early marker of disease being normal even in the case of impaired heart and is also affected by loading condition. Accordingly, other parameters beyond LVEF have been studied to assess systolic function.The assessment of myocardial deformation is based on the arrangement of myocardial architecture. The LV myocardial architecture has an oblique helical fiber arrangement with a right-handed helix in the subendocardial region that gradually changes into a left-handed helix in the subepicardial region. Myocardial fibers of the LV consist of endo- and epicardial layers composed of longitudinal fibers and mid-myocardial layers formed by circumferential fibers. In systole, the shortening of longitudinal fibers causes the displacement of the LV basal plane towards the apex, while the shortening of circumferential fibers induces radial thickening. Deformation in both of these planes reduces LV during systole –38. AccoTechnological advance made possible the assessment of myocardial deformation in different planes corresponding to LV fiber orientation, and several echocardiographic methods have been applied.Doppler myocardial imaging (or tissue Doppler imaging (TDI)) examines the longitudinal component of myocardial contraction throughout the cardiac cycle. TDI measurements are more sensitive than conventional echocardiography for detecting early myocardial alterations , 44. HowThe more recent method of two- and three-dimensional speckle tracking echocardiography (STE) has completely revolutionized the myocardial deformation imaging field providing an estimation of myocardial deformation by measuring strain and strain rate. Strain is described as a deformation of the myocardium during the cardiac cycle in the longitudinal, circumferential, and radial planes. Strain is defined as the change in length of a myocardial segment relative to its resting length while a strain rate is defined as the rate of such deformation .Evidences demonstrated that global longitudinal strain (GLS) can be more sensitive to detect LV impairment than LVEF providing better insight into myocardial impairment. GLS can be altered in patients with HFpEF suggesting unrecognized myocardial systolic dysfunction and can be associated with worse clinical outcomes , 46, 47.Speckle tracking-based deformation analysis predominantly relies on semi-automatic image segmentation (delineation) and quantification techniques, providing a reproducible platform. Different analysis algorithms from different vendors may affect the reproducibility among different echocardiography; however, recent standardization should improve the robustness of the technique .Despite the fact that echocardiography is the first-line imaging method in the workup of HF patients, however CMR has emerged as an indispensable diagnostic tool over the last few years.CMR provides at the same time information on chamber morphology, dimension and systolic function, myocardial perfusion, valve anatomy and function, and vessel and tissue characterization. Several sequences are available, and they can be combined in different protocols in order to answer to a clinical question .CMR is considered the best alternative imaging modality to provide accurate and reproducible measurements on bi-ventricular dimension and systolic function in patients with poor acoustic window or doubtful echocardiogram (class I evidence C)  due to eHowever, the added value of the technique is the possibility to non-invasively tissue characterization of the myocardium. CMR allows the detection of myocardial focal abnormalities, such as edema, fat, iron overload, and fibrosis. Particularly the late gadolinium enhancement (LGE) technique represents the keystone of tissue characterization and provides insights into the underlying causes of myopathy, distinguishing between ischemic and non-ischemic etiologies. The presence, the distribution, and the extent of LGE provide information on the underlying etiology to exclude conditions with phenotypic overlap and, importantly, to exclude ischemic heart disease as a potentially reversible cause.Patients with an ischemic etiology of LV dysfunction demonstrate subendocardial or transmural LGE in a coronary artery distribution whereas those with non-ischemic causes have either no LGE or LGE with a non-ischemic pattern. A non-ischemic pattern can be mid-wall, subepicardial, or patchy. LGE is a robust, validated technique and its presence carries important prognostic information –53. Howeλ [λ is the partition coefficient. The myocardial intracellular volume (ICV) is calculated as 1 − ECV. This technique has been validated in against histology in several cardiac diseases [T1 mapping sequence is acquired in a single breath-hold. Within the T1 map, each given pixel value directly corresponds to its underlying T1 relaxation time that can be seen in color and formally quantified. T1 mapping is tissue-specific and increased in the presence of edema, fibrosis, and amyloid, while it is reduced in the case of iron overload or fat presence . In clinλ , where λdiseases –63, and diseases .T1 mapping holds the potential to detect myocardial changes early and carries prognostic information . RecentlIn the complexity of heart failure syndrome, identification of pathophysiology and etiology is the only way to define a correct diagnosis. Additionally, physicians must be reminded that management of HF is not just taking care of its symptoms. It is mandatory to decipher the mechanisms underlying HF that is a multiorgan syndrome. Taking into consideration the involvement of the systemic organ is the key for success. Recently, we proposed a new staging system for HF, named HLM (A-B) , 68, in HLM classification integrates clinical, laboratory, and instrumental parameters concerning the heart, lungs, and other organs. In fact, using the integration of multiple variables, HLM is aimed at going beyond the simple consideration of only the cardiac performance or the mere LVEF value or the heart-lung axis alone, operated by the most common classifications.Therefore, it is important to decipher pathophysiological mechanisms that underlie the heart damage –71; alsoOur review underlines the pitfalls of the evaluation of LVEF by two-dimensional echocardiography and shows the need to go beyond its measure in daily management of HF patients. In order to reach the best stratification of the patient and to choose the most appropriate treatment, it is fundamental to comprehend the pathophysiological mechanisms and structural and functional modifications underlying HF; also, it is essential to change our cardiocentric perspective into a holistic point of view of heart failure that, in analogy with a cancer, involves other organs such as the lungs, kidney, and liver, reducing prognosis, often independent of symptoms and LVEF value.


Type 2 diabetes mellitus (T2DM) is a major cause of heart failure (HF) with preserved ejection fraction (HFpEF), usually presenting as left ventricular (LV) diastolic dysfunction. Thus, LV diastolic function should be considered a crucial marker of a preclinical form of DM-related cardiac dysfunction. However, the impact of glycemic variability (GV) on LV diastolic function in such patients remains unclear.We studied 100 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease . GV was evaluated as standard deviation of blood glucose level using continuous glucose monitoring system for at least 72 consecutive hours. LV diastolic function was defined as mitral inflow E and mitral e’ annular velocities (E/e’), and > 14 was determined as abnormal.E/e’ in patients with high GV (≥ 35.9 mg/dL) was significantly higher than that in patients with low GV  despite similar age, gender-distribution, and hemoglobin A1c (HbA1c). Multivariate logistic regression analysis showed that GV ≥ 35.9 mg/dL  was an independently associated factor, as was age, of E/e’ > 14. In sequential logistic models for the associations of LV diastolic dysfunction, one model based on clinical variables including age, gender and hypertension was not improved by addition of HbA1c (p = 0.67) but was improved by addition of high GV (p = 0.04).Since HFpEF is a syndrome caused by diverse agents, reducing GV may represent a potential new therapeutic strategy for the prevention of the development of HFpEF in T2DM patients. Type 2 diabetes mellitus (T2DM), as well as cardiovascular disease, is a major cause of heart failure (HF), both with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF), , 2. HF a2; (5) uncontrolled hypertension > 180/100 mmHg; (6) more than moderate valvular heart disease; and (7) atrial fibrillation. All enrolled patients underwent an exercise stress screening test such as a treadmill exercise or stress myocardial perfusion scintigraphy during their hospitalization, and patients with an ischemic response were excluded. The diagnosis of T2DM was based on the World Health Organization criteria [A total of 100 DM patients were retrospectively enrolled in this study. They had been admitted to Kobe University Hospital between July 2013 and September 2015 and undergone both echocardiography and CGM. Preliminary exclusion criteria for this study were: (1) history of coronary artery disease; (2) LVEF < 50%; (3) previous history of open-heart surgery or congenital heart disease; (4) severe renal dysfunction defined as glomerular filtration rate < 30 mL/min/1.73 mcriteria . This stAll echocardiographic data were obtained by means of a commercially available echocardiographic system  within 2 weeks after admission. Digital routine grayscale two-dimensional cine loops from three consecutive heart beats were obtained at end-expiratory apnea from standard parasternal and apical views. Sector width was optimized to allow for complete myocardia visualization while maximizing the frame rate. Standard echocardiographic measurements were obtained according to the current guidelines of the American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) . SpecifiLess than 6 days of echocardiographic examination, all patients underwent CGM at least 72 h which continuously measured blood glucose level every 5 min by means of a commercially available CGM system . GV was evaluated as standard deviation (SD) of blood glucose level. The patients were then divided into two groups based on the average SD of blood glucose levels (35.9 mg/dL).2 of the model was defined as representing an incremental predictive value. For all steps, a p value of < 0.05 was considered statistically significant. All analyses were performed with commercially available software .Continuous variables were expressed as mean values with SD for normally distributed data and as medians values with interquartile range for non-normally distributed data. Categorical variables were expressed as frequencies and percentages. The parameters of the two subgroups were compared by using Student t test or Mann–Whitney U test as appropriate. Proportional differences were evaluated with Fisher’s exact test. The initial univariate logistic regression analysis to identify univariate determinants of LV diastolic dysfunction (E/e’ > 14) was followed by a multivariate logistic regression model using stepwise selection, with the p levels for entry from the model set at < 0.10. Sequential logistic models were performed to determine the incremental benefit of GV in relation to clinical variables including age, gender, hypertension, and HbA1c. A statistically significant increase in the global log-likelihood χThe baseline clinical and echocardiographic characteristics of the 100 T2DM patients are summarized in Table 2 = 11.6), showed no improvement for the addition of HbA1c , but did show improvement for the addition of high GV .Table Next, all patients were divided into two groups based on the median value of HbA1c (8.2 mg/dL). E/e’ for the high (≥ 8.2 mg/dL) and low (< 8.2 mg/dL) HbA1c groups was similar  inhibitor-enhanced glucagon-like peptide-1 may ameliorate LV diastolic dysfunction in T2DM by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis –33. TherAs already mentioned the pathogenesis of DM-related cardiac dysfunction is thought to be multifactorial, and possibly a key factor in the development of HFpEF in T2DM patients, which presents as LV diastolic dysfunction. It has also been previously reported that simple suboptimal glycemic control, such as seen in high HbA1c, was associated with the development of HF in patients with newly diagnosed DM, while a 1% reduction in HbA1c was associated with a 16% risk reduction in the development of HF in patients with newly diagnosed T2DM . Since tThis study covered a small number of patients, so that further prospective studies with larger patient populations will be needed to validate our findings. The most common parameter of GV is the mean amplitude of glycemic excursion (MAGE), which has been determined by calculating the arithmetic mean of the difference between consecutive peaks and nadir if the difference is > 1 SD of the mean glucose level . Since cGV appears to be an important associated factor for LV diastolic function in asymptomatic T2DM patients with preserved LVEF without coronary artery disease. Since HFpEF is a complex clinical syndrome, reducing GV may represent a new therapeutic strategy for the prevention of the future development of HFpEF in such patients.