Electrocardiogram is the initial test in the investigation of heart disease.Electrocardiographic changes in hypertrophic cardiomyopathy have no setpattern, and correlates poorly with echocardiographic findings. Cardiacmagnetic resonance imaging has been gaining momentum for better assessmentof hypertrophy, as well as the detection of myocardial fibrosis.To correlate the electrocardiographic changes with the location ofhypertrophy in hypertrophic cardiomyopathy by cardiac magneticresonance.This descriptive cross-sectional study evaluated 68 patients with confirmeddiagnosis of hypertrophic cardiomyopathy by cardiac magnetic resonance. Thepatients’ electrocardiogram was compared with the location of the greatestmyocardial hypertrophy by cardiac magnetic resonance. Statisticalsignificance level of 5% and 95% confidence interval were adopted.Of 68 patients, 69% had septal hypertrophy, 21% concentric and 10% apicalhypertrophies. Concentric hypertrophy showed the greatest myocardialfibrosis mass (p < 0.001) and the greatest R wave size in D1 (p =0.0280). The amplitudes of R waves in V5 and V6 were higher in apical hypertrophy, with statistical significance. Apicalhypertrophy was also associated with higher T wave negativity in D1, V5 andV6 (p < 0.001). Strain pattern was found in 100% of the patients withapical hypertrophy (p < 0.001).The location of myocardial hypertrophy by cardiac magnetic resonance can becorrelated with electrocardiographic changes, especially for apicalhypertrophy. In HCM, the ECG has not a defined pattern, and can show signs of leftventricular overload, presence of q waves, changes in the ST segment, abnormal Twaves, or be even normal in 6% of the patients.2 Electrocardiographic patterns similar to that of myocardialinfarction in young individuals can precede the echocardiographic evidence ofmyocardial hypertrophy.4Some specific electrocardiographic findings may suggest the location of hypertrophy,as well as the presence of fibrosis. Giant inverted T waves (> 10 mm) in theprecordial or inferolateral leads suggest apical involvement. Deep q waves in theinferolateral leads with positive T waves are associated with the asymmetricdistribution of the HCM, and q waves lasting more than 40 ms relate to fibrosis. TheST-segment elevation in the lateral wall can correlate to small apical aneurysms,which are associated with fibrosis.The electrocardiographic changes can lead to the suspicion of HCM, and together withthe clinical history and other imaging tests can establish the diagnosis.6Traditionally, echocardiography is the imaging test of choice to diagnose HCM,because of its wide availability and lower cost. However, the relationship betweenthe electrocardiographic changes and the morphology and severity of myocardialthickness has not been well established when assessed on theechocardiogram.2Cardiac magnetic resonance imaging has gained importance in the HCM assessment,because of its superiority in measuring the thickness of ventricular walls, mainlyin regions difficult to visualize on echocardiography, in addition to providingventricular morphology and function assessment. Detection of delayedcontrast-enhancement has prognostic value.This study was aimed at correlating electrocardiographic variables with the locationof myocardial hypertrophy assessed on cardiac magnetic resonance imaging.This is a descriptive cross-sectional study that assessed patients diagnosed with HCMand followed up at the Cardiomyopathy Sector of the Instituto Dante Pazzanese deCardiologia (IDPC), who underwent cardiac magnetic resonance imaging from January2012 to September 2015.The patients’ inclusion criteria were: age over 18 years and diagnosis of HCMconfirmed on interpretable ECG and magnetic resonance imaging performed at theImaging Sector of the IDPC. The exclusion criteria were: age < 18 years; ejectionfraction lower than 50% on cardiac magnetic resonance imaging; resistant arterialhypertension; presence of coronary artery disease, characterized by a coronarylesion greater than 50% on angiography; presence of Chagas disease; previousdiagnosis of amyloidosis; endomyocardial fibrosis; Fabry disease; presence ofdefinitive pacemaker; and septal myectomy or alcoholization prior to cardiacmagnetic resonance imaging.The HCM database of the Cardiomyopathy Sector of the IDPC was analyzed, and themedical records of 112 patients meeting this study inclusion criteria, which werestored at the Sector of Medical File and Statistics (SAME) of the IDPC, wereassessed. After reviewing the medical files, 44 patients were excluded from thestudy.7 The ECG reportcomprised the following variables: rhythm, heart’s QRS axis, ventricular and atrialoverloads, intraventricular blocks, presence of strain, R wave size (millimeters) inleads DI, V1, V5 and V6, and T wave size (millimeters) in leads D1, V5 and V6.The ECGs previously performed for the outpatient clinic visit at the CardiomyopathySector were reviewed by the chief of the Tele-Electrocardiography Sector of theIDPC, in accordance with the 2016 Brazilian Guidelines on ECG Analysis andReport.8and the presence of delayed enhancement, as well as quantification of the fibrosismass in grams. The 17 segments were grouped into five regions: anterior, inferior,lateral, septal and apical. .For attribute variables, the results were presented as percentages and frequency.Fisher-Freeman-Halton exact test was used to assess the statistical significancebetween the groups. Statistical significance level of 5% and 95% confidenceinterval were adopted.The findings were recorded in an electronic spreadsheet of Microsoft OfficeExcel, version 2013e, and the Statistical Package for the Social Sciences(SPSS), version 21.0 for Windows®, was used for analysis.This study assessed 70 patients, 55.9% of the female sex, with a mean age of 51.3years (ranging from 20 to 81 years). Of the six location patterns of hypertrophy,only three were found: apical (10%), concentric (21%) and septal (69%). Most patients (81.4%) showed delayed enhancement on magnetic resonance imaging, andall patients with concentric hypertrophy had fibrosis. In quantifying the mass offibrosis according to the location of hypertrophy, the highest mean (57.1 g) wasobserved in concentric hypertrophy as compared to the other locations (p = 0.001).The concomitant presence of right ventricular hypertrophy on magnetic resonanceimaging was found in 35.7% of the patients with concentric hypertrophy, showingstatistical significance (p = 0.0447) as compared to septal and apicalhypertrophies.Patients with apical hypertrophy more frequently had atrial fibrillation (14.3%),preserved heart axis being identified in 100% of the cases. Such findings, however,had no statistical significance .Regarding ventricular overloads, there was higher prevalence of both left and rightventricular overloads  in concentric hypertrophy,with no statistical significance .The strain pattern showed statistical significance between the types of hypertrophy(p < 0.0001), being present in 100% of the apical hypertrophy cases and in 71.4%of the concentric hypertrophy cases.Left atrial overload was more frequent in apical hypertrophy (42.9%), with nostatistical significance (p = 0.4082). However, right atrial overload was rare,being identified in only two patients with septal hypertrophy.Intraventricular blocks, such as left bundle-branch block, right bundle-branch blockand left anterior hemiblock, were infrequent in the three types of hypertrophy, withno statistical difference between the groups. The analysis of the size of the R wave in lead DI showed higher mean (15.6 mm) inconcentric hypertrophy, and lower mean in septal hypertrophy (10 mm), with asignificant difference between the three groups (p = 0.0280). In lead V1, the R waveshowed no difference in its size (p = 0.9563).As compared to septal and concentric hypertrophies, apical hypertrophy showed greaterR wave amplitude in leads V5 and V6 , withstatistical significance .Regarding ventricular repolarization, apical hypertrophy correlated with the highestT wave negativity in DI (-3.8 mm), V5 (-10.2 mm) and V6 (-7.9 mm), with statisticalsignificance in the three leads (p < 0.001). 2Analysis of the patients with HCM showed a mild predominance of the female sex(55.9%), which differs from that reported in other studies.9Mid-ventricular and lateral involvements, not identified in this study, are rare,with reported prevalence of 1% to 2% of the cases.10The distribution of myocardial hypertrophy found in this study by use of magneticresonance imaging showed predominance of the septal location of hypertrophy (69% ofthe cases), followed by the concentric (21%) and apical (10%) locations, similar tothat reported in the literature.11 in a prospective study with 53 patients with HCM undergoingmagnetic resonance imaging with gadolinium, have concluded that the presence offibrosis relates to the occurrence of ventricular arrhythmias, ventriculardilatation and sudden death. Concentric hypertrophy showed a bigger mass of fibrosisas compared to that of the other hypertrophy locations. The R wave amplitude in DIwas higher in concentric hypertrophy, showing a possible electrocardiographicpattern correlated with that location.The presence of delayed enhancement on cardiac magnetic resonance worsens theprognosis of patients with HCM. Moon JC et al.,12 The mean R waveamplitude in V5 and V6 in the apical region was 26 mm, which is similar to thatdescribed by Yamaguchi et al. in patients with apical hypertrophy confirmed on theechocardiogram.12 Theanalysis of the R wave in V1 failed to show a good correlation with the anatomicpattern of hypertrophy.However, in leads V5 and V6, the R wave amplitude measured in millimeters showed asignificant correlation with apical hypertrophy, in accordance with the findings ofother studies.13 assessing 118patients with HCM, have observed that negative T waves associated with apicalhypertrophy (p = 0.009), corroborating the present study. Giant T waves, describedas inversion ≥ 10 mm in any anterior lead, were also associated with apicalhypertrophy, being found in the patients of that study in leads V5 and V6.15 The same relationship has been reported by Song etal.,15 studying 70patients, who have evidenced a correlation of a deep negative T wave with apicalhypertrophy on magnetic resonance imaging (p = 0.018).In addition, apical hypertrophy was related to higher T wave negativity in the leadsDI, V5 and V6 . Chen X etal.,16 analyzing 864 patients with HCM, have found that samecorrelation of the strain pattern with apical hypertrophy; however, that wasassessed by use of echocardiography (p < 0.001). The specific analysis of thatelectrocardiographic finding and its correlation with magnetic resonance imagingfindings in HCM have not been found in the literature.Regarding the analysis of the strain pattern on ECG (change in the ST segment and Twave), that electrocardiographic finding showed a 100% correlation with the anatomiclocation of apical hypertrophy of the left ventricle. In patients with concentrichypertrophy, that pattern of ventricular repolarization change was found in 71% ofthe cases, while in the septal pattern, only in 28% of the cases, with statisticalsignificance. Sung-Hwan Kim et al.,17Electrocardiographic left ventricular overload was more frequently found in patientswith the concentric pattern of hypertrophy (71%) than in the others (42%), but therewas no statistical significance in those correlations. Previous studies have onlyassessed the presence or absence of electrocardiographic criteria of leftventricular overload, without comparing that finding with the location ofhypertrophy.The importance of the ECG as an initial tool to assess patients with HCM is confirmedin this study, which evidenced electrocardiographic patterns that correlate with thelocation of hypertrophy on magnetic resonance imaging.The greater amplitude of the R wave in the leads V5 and V6, and the inversion of theT wave in the leads DI, V5 and V6, already reported in previous studies, weresignificantly related to apical hypertrophy. The presence of the strain pattern onECG, when HCM is suspected, suggests apical hypertrophy on magnetic resonanceimaging.Concentric hypertrophy was associated with wide R waves in DI and a greater mass offibrosis on magnetic resonance imaging assessment.


From the resulting CINE MRI data, global left ventricular (LV) function parameters including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and left ventricular mass (LVM) were quantified. The reproducibility of the self-gated technique as well as the intragroup variability and longitudinal changes of the investigated parameters was assessed. Self-gated cardiac MRI proved excellent reproducibility of the global LV function parameters, which was in the order of the intragroup variability. Longitudinal assessment did not reveal any significant variations for EDV, ESV, SV, and EF but an expected increase of the LVM with increasing age. In summary, self-gated MRI in combination with a standardized protocol for animal positioning and scan plane planning ensures reproducible assessment of global LV function parameters.The objective of this work was the assessment of the reproducibility of self-gated cardiac MRI in mice at ultra-high-field strength. A group of adult mice ( Recent developments in genetic engineering and surgical and pharmacological methods have led to a wide selection of small rodent animal models , allowinEchocardiography using high-frequency transducers has proven to be useful in estimating LV function in mice . It is aMagnetic resonance imaging (MRI) is a noninvasive technique that uses intrinsic tissue contrast and is capable of obtaining volumetric data of the heart and the vascular system. In numerous previous studies, cardiovascular magnetic resonance (CMR) imaging has proven to be an accurate technique and is considered the gold standard for noninvasive assessment of left ventricle (LV) function parameters in humans , 5. The Where developmental studies have been done by Wiesmann et al. for assessing the cardiac function and mass between neonatal (day 3) and juvenile (week 16) age after birth , reproduFor assessment of the longitudinal reproducibility of CMR-derived cardiac parameters at 11.7 T, in this study a group of adult mice were followed for 360 days  91–PND 451) with a standardized imaging protocol for assessment of changes of cardiac parameters over time and the reproducibility of the imaging protocol.Animal experiments were approved by the regional board of Tübingen and conducted according to German law for the welfare of animals and regulations for care and use of laboratory animals. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.n = 5) were included in this study. Before the start of the study, the animals were acclimatized in a temperature-controlled environment for one week. Facility rooms were maintained at constant temperature (23°C), humidity (50% relative humidity), and 12 h light-dark illumination cycle. Access to food and tap water was ad libitum.Female wild type mice  after low flip-angle excitation. To maximize heart-phase related navigator signal alterations, a volume covering almost the complete ventricles is chosen for generation of the navigator signal. To ensure sufficient data for the subsequent multiphase reconstruction, the acquisition of the complete data set is repeated several times (number of repetitions). During retrospective reconstruction, the acquired data is sorted according to the identified cardiac and respiratory phase thus enabling the reconstruction of cardiac- and respiratory-phase resolved CINE data. Excellent myocardium-blood contrast is obtained by sequential acquisition of the slices thus minimizing the repetition time (TR) and hence saturation effects of blood. Detailed parameters of the different sequences are summarized in Imaging was performed on an 11.7 Tesla small animal MRI system . Data were obtained with a dedicated four-element array-coil optimized for imaging the mouse heart . The MR imaging protocol  compriseAll animals were scanned under isoflurane anesthesia. For initiation of the anesthesia, 5% isoflurane concentration in room air was used. For maintaining the anesthesia during the MRI, the isoflurane concentration was adapted to a value resulting in a respiratory frequency between 50 and 70 respiratory cycles per minute. Depending on the animal, isoflurane concentrations between 1% and 1.5% were required. During scanning the respiratory rate was monitored and the temperature of the animals was controlled by water heating of the animal bed. The animals were positioned in prone position carefully taking care for straight alignment of the animal with the animal support. The respiratory cushion was placed between the abdominal wall and the animal cradle at the level of the liver region to minimize its impact on the positioning of the animal in the target area.All animals were followed over 360 days and scanned following the MRI protocol mentioned above at 9 time points on 6 different days . On PND 91, PND 93, and PND 95, the entire protocol was performed twice within 2 hours, yielding 9 measurements per animal in total. Between the subsequently performed scans on PND 91, PND 93, and PND 95, the animals were completely taken out of the scanner and repositioned.http://segment.heiberg.se) [All data were carefully analyzed regarding image quality. Data sets with significant artifacts caused by unexpected animal motion in at least a single slice were excluded. In this study no rescanning of corrupted slices was performed to ensure the same imaging protocol in all animals. LV global function parameters were evaluated by tracing epicardial and endocardial borders in end-diastole and end-systole. Contours were manually identified in all short axis images from base to apex. During delineation of the endocardial contour, papillary muscles were included as part of the myocardial wall. The apical slice was identified as the most distal segment that contains LV cavity and myocardium. The basal slice was defined as the most proximal segment located above the tips of the papillary muscles at the chordae tendineae. End-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV) were determined and LV ejection fraction (EF) and end-diastolic left ventricular mass (LVM) derived. The average time for image postprocessing was about 15 min per animal. All image analyses were done blinded using the freely available software Segment version 1.9.1 (berg.se) .The data were used for assessing the (a) reproducibility or interexperiment variability of the proposed imaging approach, (b) the variability of the function parameters within a group, and (c) the longitudinal changes of the function parameters over one year.Regarding (a) the assessment of the reproducibility of the suggested imaging protocol was performed based on the comparison of the function parameters of the subsequent acquired scans performed on PND 91, PND 93, and PND 95.p values of p ≤ 0.05 being considered significant. The agreement between two measurements was assessed by mean of Bland-Altman analysis. Coefficient of variance (CoV) was calculated for assessing the variability within repeated measurements.The mean and standard deviation were computed for each parameter and each measurement point. Statistical significance of differences between subsequent measurements was assessed applying a two-way ANOVA test with Regarding (b) intragroup variability of LV function parameters was assessed for all investigated parameters  separately for all 9 time points, calculation of the respective CoV. The mean intragroup variability was derived for each parameter as the mean of the individual CoV of each of the 9 measurements.Regarding (c) longitudinal variability was assessed over 360 days. ANOVA test was used to investigate the significance of changes over the 360d period for all derived LV parameters. For PND 91, PND 93, and PND 95, only the first measurement was included in the ANOVA analysis. CoV of each LV parameter was computed for each mouse.The CoV was calculated as the fraction of standard deviation and mean of the respective function values. The reproducibility of the investigated parameters was classified according to the CoV value to excellent (CoV < 10%), very good (CoV ≥ 10% and <15%), good (CoV ≥ 15% and <20%), moderate (CoV ≥ 20% and <25%), acceptable (CoV ≥ 25% and <30%), and poor (CoV ≥ 30%).ANOVA analysis was performed with SPSS 17.0 . Bland-Altman test was performed with MedCalc 15.8 .The average total scan time resulted in about 30 minutes per animal. Mean respiratory and heart rates of the animals were 60 ± 8  cpm and 398 ± 68  bpm. All scans could be completed in all animals. In total, 7 out of the 45 image stacks were excluded from further analysis due to at least one motion corrupted slice in the short axes image stack.p value, and CoV resulting from the comparison of the two subsequent measurements are summarized in For all investigated parameters, the mean ± SD, Bland-Altman analysis, The intragroup variability for all measurements and the respective mean values are provided in The longitudinal outcome for the investigated parameters is shown in The observations are confirmed by the ANOVA analysis presented in CoV values over all time points for each investigated mouse are shown in With the increasing use of small animal model in cardiovascular research, there is an increasing demand in noninvasive methods for assessing anatomy and function of the heart and to characterize myocardial tissue. For longitudinal studies, it is of utmost importance to ensure high reproducibility of the applied method to ensure sensitive identification of different outcomes even in rather small group sizes.Currently, there is no established gold standard for assessment of cardiac function for small animals. Even though echocardiography is frequently applied, an only limited reproducibility for cardiac function parameters has been reported . FactorsWith CMR a versatile imaging tool is available, which enables noninvasive assessment of cardiac anatomy and function, and in combination with advanced imaging techniques has the potential to enable myocardial tissue characterization. In direct comparison with high-frequency echocardiography, MRI appears especially advantageous in animals cardiac pathologies impacting left ventricular geometry of regional function, cases in which echocardiography often lacks accuracy . In partCardiac MRI (CMR) in small animals was known as a cumbersome procedure suffering from low SNR, high respiratory and cardiac rates, distorted ECG signals by the magnetohydrodynamic effect, and currents introduced by the rapid gradient switching making the required cardiac synchronization difficult. With the advent of ultra-high-field MR systems SNR and hence spatial and temporal resolution of the CMR substantially increased over the last decade enabling high-quality assessment of cardiac function . With thWith the increasing use of CMR, knowledge of its reproducibility is gaining importance. Reproducibility studies of murine CMR have proved excellent intra- and interobserver variability, and correlation of CMR-derived left ventricular mass with postmortem measurements from ECG-synchronized acquisitions , 25. RecThe goal of the presented study was to investigate the long-term reproducibility of cardiac function parameters derived from self-gated CMR. With the suggested imaging protocol, the interexperiment, intragroup, and longitudinal reproducibility could be quantified. For all measurement, scanning was performed according to a standardized protocol including animal positioning, scan orientation planning, and data evaluation. From the initial 6 measurements  excellent reproducibility was obtained for EF and LVM, very good for the EDV and SV, and moderate reproducibility for the ESV. In all cases no significant differences were found between the six measurements proving rather high interexperiment reproducibility. The observed values agree well with Vanhoutte et al. showing slightly lower variability for LVM, SV, and EF. Intragroup variability was assessed independently for each time point. With mean values between 7.38 (dEF) and 24.12 (dESV) the resulting intragroup variability was similar to the interexperiment variability. Long-term assessment of the variability (PND 91–PND 451) revealed highly reproducible cardiac function parameters over a one-year period and sensitive identification of even small changes as shown for the LVM, where a significant increase over time could be identified, while all function parameters remained unchanged.From the data presented it is obvious that the EDV and the LVM can be quantified with highest fidelity and resulting interexperiment variability is excellent. ESV resulted as most critical parameter but still showed moderate (<25%) variability. This may be caused by several reasons. As the temporal resolution is limited and the cardiac cycle was only resolved with 20 cardiac phases, the rather high variability of the heart rate introduced different accuracy in defining the end-systolic phase. Furthermore, due to flow artifacts within the LV cavity and the smaller end-systolic volumes, errors introduced by partial volumes effect or erroneous contoured endocardial borders especially in the most apical and basal slices introduce a larger absolute error in the derived volumes as for the EDV.The resulting low interexperiment and intergroup variability indicate that, by using a standardized animal positioning, scan orientation planning, and data analysis approach, excellent reproducibility can be achieved in murine CMR even for long-term studies.In conclusion, considering the good inter- and intraobserver reproducibility reported by other groups  and the


Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs.For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure–volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction.At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure . TTE and ex vivo analyses confirmed severe concentric LV hypertrophy . The LV and RV mass increased significantly, paralleled by increased isovolumic relaxation constant (tau). Histological analyses confirmed substantial fibrosis and myocyte hypertrophy in both LV and RV. Expressions of ANP, BNP, and miRNA-29a were up-regulated, while SERCA2a and miRNA-1 were down-regulated. Plasma NGAL levels increased gradually, while the elevation of NT-proBNP was detected only at the 5-month FUP.These data prove that percutaneous artificial aortic stenosis in pigs is useful for inducing clinically relevant progredient heart failure based on myocardial hypertrophy and fibrosis.The online version of this article (doi:10.1186/s12967-017-1299-0) contains supplementary material, which is available to authorized users. Cardiac hypertrophy is an adaptive response to several cardiovascular disorders including volume- or pressure overload, cardiomyopathies, gene mutations, or loss of contractile mass after myocardial infarction . HypertrMyocardial fibrosis is characterized by activation of fibroblasts to a myofibroblast phenotype, and diffuse interstitial collagen deposition. On the molecular level, myocardial fibrosis is the result of the imbalance of pro-fibrotic factors such as growth factors and hormones, which result in enhanced synthesis of cross-linked collagen types I and III, and a reduced collagen degradation by matrix metalloproteinases and anti-fibrotic factors, such as adipokines, or natriuretic peptides .Blocking neurohumoral activation and relieving hemodynamic overload is the current standardized treatment of heart failure in the clinical practice. However, because of the molecular complexities of cardiac hypertrophy, fibrosis, and heart failure, new strategies are focusing on intervention on the intrinsic cardiac responses at the cardiomyocyte, interstitial and the intravascular level. In order to test new potential treatment regimens, adequate and meaningful animal models are necessary.To mimic secondary cardiac hypertrophy, surgical interventions in rodents are frequently used . A partiSurgical aortic banding was shown to trigger cardiac hypertrophy in pigs , inducinWe aimed to develop a large animal model of percutaneous artificial aortic isthmus stenosis induced by percutaneous implantation of peripheral bare metal stents (BMS) in descending aorta of juvenile pigs as the constant size of stent in growing pigs results in an antegrade partial obstruction of the aortic flow with gradual increase in afterload. With this method, we were able to successfully create chronic LVH, diastolic dysfunction and secondary pulmonary hypertension predicting HFPEF for use in translational research.Figure 2 and 0.5 vol% N2O. During anesthesia, continuous monitoring of the O2 saturation and ECG were performed. After surgical preparation of the right femoral artery and vein, 200 IU/kg unfractionated heparin was administered intravenously, and 6F introducers  were placed in both vessels. In order to prevent acute or subacute stent thrombosis, dual oral antiplatelet medication  was given for 1-month after stent implantation, followed by continuous treatment with 100 mg per os aspirin until the end of the experiment.Domestic pigs  were fasted overnight and were sedated with 12 mg/kg ketamine hydrochloride, 0.04 mg/kg atropine and 1.0 mg/kg xylazine, followed by intratracheal intubation. The anesthesia was then continued with 1.5–2.5 vol% isofluran, 1.6–1.8 vol% OTransthoracic echocardiography (TTE)  was performed at baseline, and at the 2, 3, 4 and 5 month FUP to measure left ventricular (LV) diastolic wall thickness of the septum and posterior wall in M-mode and 4-chamber view, and to measure the diastolic function of the left ventricle by pulsatile wave Doppler, including A- and E-wave velocity and e′.Right heart catheterization was performed via 5F pigtail  catheter, and the pressures of the right atrium (RA) and ventricle (RV) and pulmonary artery (PA) were measured. The left heart cathetherization was performed with another 5F pigtail catheter  measuring the pressures of the left ventricle (LV), ascending and descending aortae immediately after the arcus aortae  and at the diaphragma level . Pressure–volume (PV) loop investigation was performed using the Powerlab Equipments and software, adapted for large animals .After completing the baseline investigations, bare metal stents  were implanted in the descending aorta immediately under the arcus aortae Figs.  and 2 in2 and 0.5 vol% N2O), the pigs were administered an additional dose of intravenous heparin . Euthanasia was performed by giving 10 mL intravenous saturated potassium chloride (10%), in accordance with accepted guidelines.After the final MRI investigation at the 5-month follow-up, during continuous deep anaesthesia  and post-stent  in HYPI animals, and at the corresponding places in controls. Mild oversizing of the stent was chosen to avoid slipping of the stent to a distal location.Additionally, aortography by computer tomography, intraluminal echocardiography (ILE) and magnetic resonance imaging with late enhancement (MRI + LE) were performed to measure stenosis grade, LV and RV systolic function and myocardial fibrosis at the end of the experiments. The final CT and MRI + LE was performed within 1 day of angiography and final invasive measurements, followed by immediate scarification of the animals.Descriptions of the imaging modalities are detailed in the Additional file The animals were sacrificed 5 months after stent implantation, and the hearts were explanted. Myocardial tissue and plasma samples were collected for further analyses. Myocardial tissue samples from the LV, RV, RA and left atrium (LA) were immediately transferred to either RNAlater solution  or 7.5% formalin. For histological sections, tissues were embedded in paraffin and cut to 4–5 µm slices. For quantification of collagen and fibrosis, the samples were stained with HE, PicroSirius Red and MOVAT pentachrome and microscopy photographs were taken on an Olympus microscope IX83. For histological analyses, samples with similar orientation and with interstitial collagen staining were selected. Fibrosis, i.e. collagen quantity, was assessed by computerized planimetry by using ImageJ using thresholding of stained images. Myocyte cross-sectional areas were calculated with Olympus CellSens Dimension software by manually defining cell borders, using an average of at least forty cells per sample.The animal studies were approved by the local Ethical Committee of the Experimental Animal Care Committee of the University of Kaposvar, Hungary.For RNA isolation, tissue samples of around 25 mg were cut to small pieces, transferred to 700 µL Qiazol solution and homogenized using a Precellys system . Total RNA including small RNA was extracted using the miRNeasy Mini Kit  on a Qiacube according to the manufacturer’s instruction. RNA quantities were assessed on a Nanodrop 1000 (Thermo Fisher). RNA quality was checked on RNA Nano chips on the Agilent 2100 Bioanalyzer (Agilent Technologies). All samples resulted in RIN values over 7 and intact 18S and 28S bands.For mRNA quantification, RNA was transcribed to cDNA using the Qiagen QuantiTect Kit according to the manufacturer’s instructions and qPCR was performed using the Qiagen qPCR Sybr Green Kit with gene specific primers  on an Applied Biosystems 7500 Fast qPCR system (Thermo Fisher). The mean of two technical replicates was used for each individual sample. A standard curve was prepared and run for each gene for assessing PCR efficiency. Expression quantities are expressed relative to beta-Actin.Sequences of pig miRNAs were derived from the miRBase database . For miRStatistical significance was calculated by testing HYPI (n = 7) vs control animals (n = 5) using one-way ANOVA with repeated measurements, testing the between-group differences. In case for which the difference was significant, we supplemented the statistical comparison with two-sided t-tests. For statistical comparison of the groups, the parameters were assigned to the following imaging clusters: TTE, invasive pressure measurements, cardiac MRI, PV loop, histology, circulating biomarker and qPCR. Interdependent parameters determined from the same curve or figure  were accounted as one measurement. The levels of statistical significance were determined after Bonferroni correction for the following imaging groups: invasive pressure measurements (p < 0.005), cardiac MRI (p < 0.01), PV loop measurements (p < 0.01) and qPCR (p < 0.01). For TTE, histology and circulating biomarker comparisons (≤ 5 parameters were compared) p < 0.05 was considered as statistically significant. All analyses were performed by an independent observer, who was unaware of the treatment groups.The diameters of the descending aorta are listed in Table Serial TTE revealed developing severe concentric LVH with an end-diastolic septum and posterior wall thickness of 19.6 ± 2.2 and 15.8 ± 1.3 mm , respectively, in the HYPI group at the final follow-up, in contrast with the normal wall thickness in controls . The final E/A ratio was 0.92 ± 0.56, E/e′ ratio 9.2 ± 1.5  in 2 animals , which, however, did not mitigate the LVH development.Serial left and right heart catheterization revealed increasing transstenotic gradient with parallel increase in LV systolic, and end-diastolic pressure, as well as significant increase in pressures in the right heart. The secondary increase in systolic and diastolic right ventricular pressure, and pulmonary pressure reached significance at the 5-month follow-up Fig. .Fig. 5aSerial data of the PV-loop measurements are shown in Table Five-month cMRI + LE showed preserved LV ejection fraction (EF), with a trend to a decrease in right ventricular EF. In parallel with the significant increase in LV mass, the LV peak filling rate decreased in the HYPI animals, confirming the TTE findings. This model might also be considered as a model of heart failure with preserved EF (HFPEF).After the 5-month follow-up, the obduction revealed macroscopic constriction of the aortic part with the stent with pre- and post-stenotic dilation of the aorta Fig. a, b. The2 vs 527 ± 122 µm2 for LV and 627 ± 91 µm2 vs 385 ± 100 µm2 for RV; p < 0.05).Histological preparations and staining of the LV myocardial tissue with PicroSirius red and an anti-collagen antibody showed a significant increase of collagen deposition as a characteristic feature of tissue fibrosis Fig. e–g. The Plasma NGAL increased significantly after 2 months, when the myocardial hypertrophy was clinically not yet pronounced, reached a plateau at 3 months Fig. a. In conTo confirm the changes associated with cardiac hypertrophy on the molecular level, we examined the expression of genes known to be up or down regulated in response to hypertrophy. As expected, the natriuretic peptide ANP and BNP, which are only marginally expressed in adult ventricular tissue under normal circumstances, show enhanced expression levels in the LV tissue in hypertrophic pigs. LV ANP expression was increased more than threefold, and BNP levels more than twofold compared to the values of the control animals Fig. a. In conWe also examined the expression of selected microRNAs, which have been described to play a role in cardiac hypertrophy and fibrosis in animal models and in the human pathologic condition. We found depletion of the cardiomyocyte growth-repressing miR-1 to 50–66% in both the LV and RV of pigs with cardiac hypertrophy Fig. b. In addFor the development of novel and better treatment options for cardiac hypertrophy and fibrosis, relevant and reliable translational animal models are necessary. Here for the first time we report a percutaneous method to create slowly developing pressure overload of the LV causing pre-stenotic systolic hypertension, myocardial hypertrophy with LV diastolic dysfunction and secondary pulmonary hypertension in a relevant translational large animal model. The internally placed stent, in-grown in the aortic wall, precluded the normal extension of the aorta during the normal body growth. Comprehensive serial invasive hemodynamic measurements with serial TTE and ILE imaging allowed detailed monitoring of the gradual development of cardiac hypertrophy and fibrosis, confirmed by cardiac MRI and CT. Together with macroscopic and histological observations, these data show that the model is closely related to the condition of human heart failure and myocardial fibrosis by hypertension and aortic stenosis. Important new insights gained from this study are the animal model of progressing heart failure, with development of postcapillary pulmonary hypertension, and high translational value for the transition of HFPEF to HFREF.Recognizing the necessity of large animals for modeling human cardiac diseases, surgical aortic banding of the aorta has been performed in pigs, inducing abrupt changes in the hemodynamics, causing acute heart failure , 15 or bThe end-diastolic volume increased in both groups, due to the regular growth of the juvenile pigs, but a trend towards LV enlargement was observed in the HYPI animals as compared to controls, with a trend to lower LV and RV EF predicting the development of heart failure with reduced ejection fraction (HFREF), if longer follow-up had been done . The traRight heart catheterization revealed a gradual increase in the RA, RV and pulmonary artery pressures, indicating development of post-capillary pulmonary hypertension, even if measurements of capillary wedge pressure were not performed. Since the animals had no primary lung diseases at the obduction, and that the pulmonary hypertension was developed in parallel with the aortic stenosis severity, we can exclude a primary pulmonary hypertension. In contrast with the DOCA-treated animals in the experiments of Schwarzl et al. , who claAccording to the echocardiographic circumferential wall thickness measurements and the invasive pressure measurements, it seems that persistent increase in blood pressure for a longer time is necessary for manifest LV wall thickening; however, a definitive timely correlation between increase in systolic blood pressure and myocardial hypertrophy requires a histological verification, necessitating the harvesting of the animals at different time-points.2+-ATPase SERCA2a is instrumental in maintaining calcium homeostasis and decreased expression and function aggravates heart failure [Histology and the changes in expression of cardiac mRNAs and miRNAs confirmed the regulation of important biomarkers for hypertrophy and fibrosis. The left ventricular expression of natriuretic peptides ANP and BNP was increased, confirming the cardiac origin of the elevated plasma pro-BNP levels. The ventricular expression of natriuretic peptides is a well-documented result of pressure- and volume stress , 19 and  failure , 20, 21. failure , and dowSimilarly, several microRNAs that are known to play a role in hypertrophy are up or down regulated. Increased expression of miR-29a is consistently found in hypertrophic animal models and in human heart failure and also with cardiac hypertrophy and fibrosis in hypertrophic cardiomyopathy patients , highligWe did not perform MRI at baseline in order to avoid exposing the small, 15 kg animals to more stress; MRI would have required either an additional anesthesia, or a longer anesthesia for transport of the intubated animals from MRI to the angiographic lab.We have measured the dP/dt both with the pigtail catheter and also with the piezo transducer of the pressure–volume loop catheter. We are aware that the pig-tail catheter may underestimate the dP/dt; however, in contrast to the pig-tail catheter, the pressure–volume loop measurements are very rarely used in humans, and we strived for optimal translational value of our experiments. Additionally, the pressures of the pigtail catheter were calibrated before each measurement. The 15 kg pigs were 1 month old, in “child age” for pigs, with somewhat lower normal systemic blood pressure, therefore the dP/dt values (derivate of systolic pressure and time) around 1000 mmHg/s measured by the pig tail catheter may be considered as being within the normal range.As the pig heart lies behind the sternum, the usual echocardiographic measurements are difficult. The measurements of the left atrium diameter were possible from parasternal short axis view, and the Doppler parameters from the apical 4-chamber views, while measurement of the other parameters were not possible for all pigs for all time points; therefore, we have not reported these parameters.Induction of gradual development of LV hypertrophy by minimally invasive percutaneous approach in our large animals successfully simulates human conditions with natural progressive sclerotizing aortic stenosis being hemodynamically compensated and asymptomatic for a long time. This model is in a good agreement with pathophysiologic concepts of myocardial hypertrophy with consequent cardiac fibrosis, hence LV dilation and postcapillary pulmonary hypertension on the molecular and physiological level, offering several molecular targets for potential antifibrotic treatment, or preventive medical approaches against complications of aortic stenosis. Our model is mainly designed for pressure overload induced cardiac hypertrophy and progressing heart failure. However, we believe it can be used as a general model to study the cellular and molecular mechanisms of cardiac fibrosis, which shares at least some common features regardless of the underlying cause .Percutaneous implantation of BMSs in the descending aorta of juvenile pigs causing slowly developing artificial aorta isthmus stenosis successfully simulates cardiac hypertrophy and fibrosis and is in good agreement with pathophysiologic concepts of human disease on the molecular and physiological level. It is thus a useful model for researching molecular mechanisms of hypertrophy and for evaluation of potential treatments.


The therapeutic strategy was chosen following a dedicated multidisciplinary team-oriented approach, including surgical valve replacement (n = 11), transcatheter valve implantation (n = 19), balloon aortic valvuloplasty (BAV) (n = 25) and optimal medical therapy (n = 25). Besides routine echocardiographic indices, valvulo-arterial impedance (Zva), an index of global LV afterload, was computed. There were 22 deaths over a median follow-up of 523 days. Baseline Gal-3 correlated negatively with estimated glomerular filtration rate (eGFR)  and was unrelated to age, symptomatic status, AVA index, LV ejection fraction, LV mass index or Zva. For the study group as a whole, Gal-3 tended to predict mortality : 2.03 , p = 0.09), which was abolished upon adjustment for eGFR (HR: 1.70 (0.61–4.73), p = 0.3). However, in post-BAV patients multivariate-adjusted pre-procedural Gal-3 was associated with worse survival (HR: 7.41 (1.52–36.1), p = 0.01) regardless of eGFR. In conclusion, the inverse eGFR–Gal-3 relationship underlies a weak association between Gal-3 and adverse outcome in patients with degenerative AS referred for invasive therapy irrespective of type of treatment employed. In contrast, pre-procedural Gal-3 appears an independent mortality predictor in high-risk AS patients undergoing BAV.Galectin-3 , a β-galactoside-binding lectin, has been implicated in myocardial fibrosis, development of left ventricular (LV) dysfunction and transition from compensated LV hypertrophy to overt heart failure (HF), being a novel prognostic marker in HF. Risk stratification is crucial for the choice of the optimal therapy in degenerative aortic stenosis (AS), affecting elderly subjects with coexistent diseases. Our aim was to assess correlates and prognostic value of circulating Gal-3 in real-world patients with degenerative AS referred for invasive treatment. Gal-3 levels were measured at admission in 80 consecutive patients with symptomatic degenerative AS  index: 0.4 ± 0.1 cm Galectin-3 , a β-galactoside-binding lectin, has been implicated in myocardial fibrosis, development of left ventricular (LV) dysfunction and transition from compensated left ventricular (LV) hypertrophy to overt heart failure (HF) in various experimental HF models ,2,3,4. GIn an early clinical report, Sharma et al.  describeRisk stratification is crucial for the choice of the optimal therapy in degenerative AS, affecting mainly elderly subjects with coexistent diseases, thereby posing a therapeutic challenge for cardiac surgeons and invasive cardiologists . Thus, oDemographic, clinical and echocardiographic characteristics of AS subjects are shown in Median Gal-3 level was 15.6 ng/mL  and was skewed to the right. Out of 80 subjects enrolled, 30 patients (38%)—in accordance with a previous report based on the same method of Gal-3 assay in 101 AS patients undergoing transcatheter aortic valve implantation (TAVI) —had a Gar = −0.61, p < 0.001) , being unrelated to age, symptomatic status, AVA index, transvalvular aortic pressure gradients, EF, LV mass index or valvulo-arterial impedance (Zva), a measure of global LV afterload  (< 0.001)  and posifterload .TAVI, balloon aortic valvuloplasty (BAV) and surgical valve replacement (SVR) were performed in 19, 25 and 11 patients, respectively, while 25 subjects received optimal medical therapy. Subjects who underwent BAV were significantly older compared to the remainder .In the study group as a whole, Gal-3 exhibited a borderline or weak association with all-cause mortality (22 deaths) over a median follow-up period of 523 days . However2): 1.15 , p = 0.01; eGFR: HR per decrease of 10 mL/min per 1.73 m2: 0.80 (0.59–1.07), p = 0.14).On a univariate analysis limited to 25 AS patients undergoing BAV, pre-procedural Gal-3—categorized by a cut-off value of 17.8 ng/mL—tended to predict mortality (14 deaths) during a median follow-up of 362 days . This reThe significance was maintained when other potential confounders were forced into regression models as covariates, including age, gender, NYHA functional class, AVA, EF, coexistent coronary artery disease or diabetes, and NT-proBNP levels. We identified depressed eGFR as a strong determinant of circulating Gal-3 levels in patients with symptomatic degenerative AS referred for invasive treatment. In the study group as a whole, Gal-3 weakly predicted total mortality, nevertheless, the effect was abolished upon adjustment for eGFR. However, multivariate-adjusted pre-procedural Gal-3 was associated with worse survival regardless of the degree of renal dysfunction in AS subjects undergoing BAV.To the best of our knowledge, our preliminary report is the first to demonstrate a prognostic value of Gal-3 in patients after BAV. With regard to post-TAVI subjects, there are conflicting results in terms of prognostic effects of pre-procedural Gal-3. According to Baldenhofer et al. , in 101 Our results supplement existing evidence of the close association of Gal-3 with eGFR in patients with HF ,11,19, sA predominant role of eGFR for circulating Gal-3 is well proven. Tang et al.  confirmeMechanisms of excessive accumulation of Gal-3 in renal dysfunction have not been fully elucidated so far. In HF, Meijers et al.  demonstrIn our study group as a whole, adjustment for eGFR abolished the association of baseline Gal-3 with mortality. This is in accordance with previous reports which have even suggested that the prognostic value of Gal-3in HF may be due to its association with renal dysfunction ,28. AddiAs far as the prognostic effect of eGFR in AS is concerned, baseline renal failure potently predicted 6–18-month mortality in 262 patients undergoing BAV , 274 medAdmittedly, renal effects of Gal-3 are far from being unequivocally clarified. In various experimental models, upregulation of Gal-3 in response to kidney injury was linked to either a pro-resolution role or a pro-fibrotic effect, which translated into protection from injury ,38,39 orA high restenosis rate has a profound impact on prognosis in post-BAV patients. In a histological study of aortic valves excised from patients operated upon 1–36 months after BAV, mainly due to clinical restenosis, van den Brand et al.  demonstrAdmittedly, circulating pre-procedural Gal-3 may not necessarily reflect local Gal-3 levels within the aortic valve. However, Sadaba et al.  reportedOn the other hand, our results might also result from a contribution of myocardial Gal-3 to collagen deposition and consequent myocardial dysfunction. LV fibrosis, quantified my magnetic resonance imaging, predicted mortality during a median follow-up of 2.9 years in 194 AS patients undergoing SVR or TAVI . Indeed,Nevertheless, conclusions from experimental models cannot be easily extrapolated into clinical conditions, and clinical correlates of blood Gal-3 differ between various clinical settings. Although plasma Gal-3 at Day 7 was related to myocardial extracellular volume fraction at six months in patients after acute myocardial infarction , other rBeyond valvular, myocardial and renal effects, Gal-3 upregulation in vascular myocytes may be accountable for the aldosterone-induced vascular fibrosis , which cGal-3 might also accelerate atherogenesis, thus contributing to adverse outcome. However, data on a potential role of Gal-3 in the development of plaques are inconsistent, and opposite effects were described in various models of experimental atherosclerosis ,60. As aAn independent association of Gal-3 with mortality only in post-BAV patients suggests an underlying mechanism that is limited to AS subjects undergoing BAV, i.e., contribution of Gal-3 to development of valve restenosis and subsequent HF recurrence. In contrast, alternative mechanisms would be expected to take place in all of the study subjects irrespective of type of treatment employed, including Gal-3 involvement in renal function decline, myocardial fibrosis and increased vascular stiffness with consequent progressive HF. However, the absence of an independent prognostic effect of Gal-3 for the whole study group argues against these mechanisms. Nevertheless, further investigations are warranted to validate the proposed concept in a larger group of AS patients.2/m2 body-surface area or mean transvalvular aortic pressure gradient ≥25 mmHg [We studied 80 consecutive patients  with the final diagnosis of severe or moderate symptomatic degenerative AS  referreThe study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Bioethics Committee of Jagiellonian University . All subjects gave their informed consent for inclusion to the study.Demographic and clinical patients’ characteristics, including cardiovascular risk factors and HF symptoms graded by New York Heart Association (NYHA) functional classification were registered at admission. Maximal and mean transvalvular aortic pressure gradients were derived by the modified Bernoulli formula from continuous Doppler recordings and AVA index was calculated by the standard continuity equation. LV volumes and EF were computed by the biplane method of disks summation (modified Simpson’s rule), as currently recommended , and LV In addition to routine echocardiographic parameters of AS and LV structure and function, Zva, an index of global LV afterload, was computed from brachial systolic pressure, mean transvalvular pressure gradient and LV volumes as proposed previously ,56,58.Blood was drawn from an antecubital vein for routine biochemical analyses and extended assays. Gal-3 was measured by means of an automated enzyme-linked fluorescent assay    and NT-pThe study subjects underwent a complex diagnostic workup in our center. The therapeutic strategy was chosen following a dedicated multidisciplinary team (Heart Team)-oriented approach, including SVR, TAVI  and BAV  . Those cr) for continuous and ordinal variables, respectively. Gal-3 and NT-proBNP concentrations were natural logarithmically (log) transformed owing to their right-skewed distributions. Intergroup comparisons were performed by 2-tailed Student’s t-test and chi-square test for continuous and categorical variables, respectively.Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range for non-normally distributed data. The accordance with a Gaussian distribution was checked by the Liliefors test. Categorical data were shown as numbers and percentages. Bivariate correlations between patients’ characteristics and levels of Gal-3 and NT-proBNP were estimated by Pearson’s or Spearman’s correlation coefficients (p-value below 0.05 was assumed significant; Bonferroni correction for multiple testing was used with regard to correlates of Gal-3 and NT-proBNP levels and intergroup comparisons according to treatment modality.The predictive ability of Gal-3 was tested by comparing Kaplan–Meier survival curves by the log-rank test with Gal-3 levels categorized according to a cut-off value of 17.8 ng/mL, previously proposed for risk stratification in patients with established HF ,11. DeatIn degenerative AS, plasma Gal-3 is mainly determined by the degree of coexistent renal insufficiency, being independent of symptomatic status, stenosis severity, valvulo-arterial impedance and LV hypertrophy or dysfunction. The inverse eGFR–Gal-3 relationship underlies a weak association between Gal-3 and adverse outcome in patients with degenerative AS referred for invasive therapy irrespective of type of treatment employed. In contrast, multivariate-adjusted pre-procedural Gal-3 appears an independent mortality predictor in high-risk AS patients undergoing BAV.


Commonly, a series of T2 weighted images with steady-state free-precession (SSFP) are acquired after T2 magnetization preparation (T2Prep) with different echo times. Conventionally, a single slice per breath-hold is acquired to image one single slice. Because inflammation/edema is often regional, multiple breath-holds are needed to cover the entire ventricle. The slice-interleaved T2 mapping sequence was recently proposed to image multiple slices in a single scan by using a slice-selective T2Prep. While accuracy of this sequence to quantify T2 was previously studied, the measurement reproducibility is not known. Therefore, we sought to investigate the reproducibility of myocardial T2 mapping using the slice-interleaved T2 mapping sequence.Myocardial T2 sequence was repeated twice. Subsequently, subjects were removed from the scanner and repositioned, followed by another 2 repetitions of the same scan. The following imaging parameters were used: In-plane resolution = 2.1 × 2.1 mm2, slice thickness = 8 mm, slice gap = 4 mm, Field of View = 320 × 320 mm2, TR/TE/α = 2.8 msec. / 1.38 msec. /55°, SENSE-rate = 2.3, and acquisition window = 191 ms, bandwidth = 1879.7 Hz/pixel. Motion correction was performed between different images. T2 maps were calculated using a 3-parameter fit model. The epicardial and endocardial contours in the left ventricle were manually drawn in 5 short axis-slices to calculate global and slice-based myocardial T2 values. Coefficient of variation (CV) analysis for each slice was generated to assess the variability. Bland-Altman plots were used to test for significant differences between repetitions, sessions and days.Eleven healthy subjects  were imaged on 2 different days with the same scan protocol using a 1.5T MRI scanner (Philips Achieva). On each day, slice-interleaved T2 values for different imaging sessions, averaged over all subjects and low CVs between subjects (7.2 ± 4.3%). There were low CVs between days (6.3 ± 4.0%) and between sessions (5.0 ± 4.3%). Fig. 2 values between first scan of day 1 and day 2 (A), between first scan of session 1 and session 2 (B), and between scan 1 and 2 within each first session (C).Figure 2 mapping sequence yields reproducible T2 measurements with highest CV of 7.2 ± 4.3% for between day scans.Slice-Interleaved T


Diastolic dysfunction of the left ventricle is common but frequently under-diagnosed. Particularly in advanced stages affected patients may present with significant functional tricuspid regurgitation (TR) as the most prominent sign on echocardiography. The underlying left ventricular pathology may eventually be missed and symptoms of heart failure are attributed to TR, with respective therapeutic consequences.The aim of the present study was to determine prevalence and mechanisms underlying TR evolution in heart failure with preserved ejection fraction (HFpEF).Consecutive HFpEF patients were enrolled in this prospective, observational study. Confirmatory diagnostic tests including echocardiography and invasive hemodynamic assessments were performed.Of the 175 patients registered between 2010 and 2014, 51% had significant (moderate or severe) TR without structural abnormalities of the tricuspid valve. Significant hemodynamic differences between patients with and without relevant TR were encountered. These included elevated pulmonary vascular resistance (p = 0.038), reduced pulmonary arterial compliance , and elevated left ventricular filling pressures (p = 0.039) in the TR group. Multivariable binary logistic regression analysis revealed diastolic pulmonary artery pressure (p = 0.029) and PAC (p = 0.048) as independent determinants of TR.Patients were followed for 18.1±14.1 months, during which 32% had a cardiac event. While TR was associated with outcome in the univariable analysis, it failed to predict event-free survival in the multivariable model.The presence of ´isolated´ functional TR should prompt the suspicion of HFpEF. Our data show that significant TR is a marker of advanced HFpEF but neither an isolated entity nor independently associated with event-free survival. Diastolic dysfunction of the left ventricle that may convert into the clinical picture of heart failure with preserved ejection fraction (HFpEF) is a growing health care problem , 2. We hThe present study was undertaken in order to determine the prevalence of significant TR in HFpEF patients, the underlying mechanisms, and its impact on event-free survival. This was a prospective observational study performed at the Medical University of Vienna, approved by the local ethics committee . All participants gave written informed consent.After thorough baseline evaluation, patients were followed by ambulatory visits and phone calls at 6-month intervals. A combined endpoint consisting of hospitalization for heart failure or death from cardiac causes was defined as the main outcome measure. Endpoints were adjudicated by our adjudication committee consisting of CZT and AAK, who were blinded to hemodynamics and other patient characteristics. An age-matched control group was also assessed with respect to clinical characteristics and imaging parameters.Consecutive patients with HFpEF were enrolled. HFpEF was diagnosed in the presence of: 1) symptoms or signs of heart failure; 2) normal or mildly reduced LV systolic function (LV ejection fraction (EF) >50%); and (3) evidence of abnormal LV relaxation or diastolic stiffness [ symptoms normal o1 <60% of predicted, restrictive lung disease with TLC <60% of predicted and / or current O2 therapy were excluded from the study.Reasons for exclusion were: significant coronary artery disease as diagnosed by coronary angiography, significant aortic or mitral valve disease, congenital heart disease, and cardiac amyloidosis as diagnosed by cardiac magnetic resonance imaging (CMR) and / or endomyocardial biopsy. Furthermore, patients with chronic lung disease such as bronchial asthma or chronic obstructive pulmonary disease (COPD) with FEVThe hemodynamic diagnosis of HFpEF was confirmed, if the pulmonary artery wedge pressure (PAWP) exceeded 12 mm Hg [All echo studies were performed by board certified physicians, using high-end scanners such as GE Vivid 5 and Vivid 7 . The evaluation included M-mode and 2-dimensional echocardiography, as well as conventional and color Doppler ultrasonography according to current recommendations –11.TR was quantified by an integrated approach  9, 11, , 11, 12.LVEF was assessed with the biplane Simpson´s method. Right ventricular (RV) function was assessed by the percentage RV fractional area change (FAC), defined as (end-diastolic area—end-systolic area) / end-diastolic area x 100, according to recent recommendations . In addiImaging and hemodynamic variables were split into two groups: 1. influenced by TR (i.e. TR- dependent) and 2. not influenced by TR (TR- independent). Changes in right heart segments and pressures were considered as TR- dependent, while pulmonary vasculature and left heart segments were defined as TR- independent.For right heart catheterization a 7F Swan-Ganz catheter  was inserted via a jugular or femoral access. Filling pressures were averaged after recording of eight heart cycles using CathCorLX . PAWP, pulmonary arterial pressure (PAP), and cardiac output (CO), were determined. CO was measured by both thermodilution and Fick method. Simultaneously, all patients underwent direct assessment of LV filling pressures, followed by coronary angiography. Standard formulae were used for the calculation of hemodynamic parameters, 17.CMR was primarily used as a complimentary method for the assessment of RV function. All patients without pacemaker or other precluding conditions underwent CMR at baseline, using a 1.5-T scanner . Functional and late gadolinium enhancement imaging studies were performed according to standard protocols . RV dysfCategorical variables were reported in percent and/or total numbers. Continuous data are presented as mean ± standard deviation. Baseline characteristics were compared using chi square or Fisher´s exact test for categorical variables and Wilcoxon two sample test for continuous variables. Variables were stratified into TR-dependent  and RV size, RV function, RA pressure, and PAP) and TR-independent  and STATA version 12 . Statistical significance was set at p<0.05 for all tests. P-values were considered exploratory.Between January 2010 and November 2014, 175 consecutive patients with a confirmed diagnosis of HFpEF and 45 age-matched control subjects were registered. Clinical and imaging characteristics of patients and controls are summarized in Tables Baseline characteristics of HFpEF patients, stratified by tricuspid regurgitation severity, are displayed in In brief, patients with relevant TR were older (p = 0.026), more frequently presented with atrial fibrillation (p<0.001), and renal dysfunction (p = 0.008). Furthermore, TR patients were more symptomatic as measured by NYHA functional class (p = 0.028), had lower systolic blood pressures (p = 0.012), and shorter 6-minute walk distances (p = 0.036).Left atrial (LA) chamber dimensions were also enlarged in TR patients (p = 0.003) reflecting elevated LV filling pressures. Further significant differences were found with respect to interventricular septum thickness (p = 0.027) and E/A ratio (p<0.001).While TR was associated with outcome in the univariable analysis, it failed to predict event-free survival in the multivariable model. Independent predictors of cardiac events or death included 6-minute walk distance (p<0.001), chronic obstructive pulmonary disease (p = 0.010), NT-proBNP (p<0.001), E/A ratio (p = 0.003), RV dysfunction (p = 0.011) and systolic PAP (p<0.001).We suggest that “isolated” functional TR is a feature of HFpEF. In fact, we demonstrate here that the evolution of TR is associated with only subtle hemodynamic changes, such as reduced PAC and elevated PAP in the presence of elevated LV filling pressures. Furthermore, we show that the presence of significant TR indicates adverse outcome but is not independently associated with event-free survival.Significant TR is a common finding , and hasWe and others  have obsDespite well-established diagnostic criteria for HFpEF , 28 the In a recent publication , potentiPAC in post-capillary pulmonary hypertension is dependent on PAWP . Indeed,With respect to event-free survival, relevant TR failed to predict outcome in the Cox regression analysis . This isIn contrast to non-TR patients, those with significant TR had larger right heart dimensions and worse RV function by echo as well as CMR studies. RV dysfunction was an independent predictor of event-free survival in the present study , confirmHFpEF is characterized by impaired left ventricular (LV) diastolic function due to abnormal relaxation and increased chamber stiffness. The consecutive rise in LV filling pressure results in a passive rise of pulmonary arterial pressure . As a consequence, pulmonary vascular compliance declines and adds to the increasing resistance against the right ventricle . Remodeling of the pre-capillary pulmonary vascular bed may occur as an additional mechanism aggravating RV pressure overload (Panel C). The RV fails to compensate pressure overload and dilates. Tricuspid annular dilatation and distortion of the subvalvular apparatus lead to increasing tricuspid regurgitation and consecutive right heart failure (Panel D).Reprinted with permission from John Wiley and Sons, from Aschauer et al. , licenseThe present study has been undertaken in a single center with a relatively small sample size. A center-specific bias cannot be excluded. However, the major advantages of limiting data collection to a single center are 1. inclusion of a homogenous patient population, 2. constant clinical routine, 3. constant quality of assessment techniques and 4. constant follow-up.CO derived by the thermodilution method may be confounded by the presence of relevant TR. However, there was a tight correlation between this method and additional CO measurements, including the Fick method  and the CMR-derived CO . Parameters of LA function have not been assessed in the present study.The diagnosis of ´isolated´ functional TR should prompt further evaluation of the LV, in particular with respect to the presence of LV diastolic dysfunction. In addition to non-invasive assessment, right heart catheter to determine the relation between pulmonary pressures and flow should be considered, since only subtle changes may be associated with relevant TR. Although patients with significant TR face a dismal prognosis, TR itself is not independently associated with outcome. Our data suggest that isolated TR is a bystander of HFpEF and the necessity of therapeutic interventions, such as tricuspid valve surgery, should be questioned.


The capabilities of the 2D segmental areas (p<0.011) may be equivalent to those of 3D segmental analysis  for differentiating the two groups . The proposed method is superior to the conventional 17‐segment in relation to reflection of patient‐specific morphological variation and allows to obtain a more precise mapping between segments and the AHA recommended nomenclature. It can be used to differentiate severer AS patients and normal controls and also helps to understand the left ventricular morphology at a glance.The purpose of this study was to develop and validate cardiac computed tomography (CT) quantitative analysis software with a patient‐specific, 17‐segment myocardial model that uses electrocardiogram (ECG)‐gated cardiac CT images to differentiate between normal controls and severe aortic stenosis (AS) patients. ECG‐gated cardiac CT images from 35 normal controls and 144 AS patients were semiautomatically segmented to create a patient‐specific, 17‐segment myocardial model. Two experts then manually determined the anterior and posterior interventricular grooves to be boundaries between the 1st and 2nd segments and between the 3rd and 4th segments, respectively, to correct the model. Each segment was automatically identified as follows. The outer angle of two boundaries was divided to differentiate the 1st, 4th, 5th, and 6th segments in the basal plane, whereas the inner angle divided the 2nd and 3rd segments. The segments of the midplane were similarly divided. Segmental area distributions were quantitatively evaluated on the bull's‐eye map on the basis of the morphological boundaries by measuring the area of each segment. Segmental areas of severe AS patients and normal controls were significantly different : 87.57.N‐, 87.57.R‐, 87.57.qp The bull's‐eye map, a polar plot from tomographic images of the left ventricle (LV), has been used for regional analysis of LV function or myocardial perfusion for more than 20 years.Association (AHA) in 2002For the bull's‐eye map, Cain et al.There have been several studies of patient‐specific bull's‐eye maps of the LV.The aim of the present study was to propose a novel 17‐segment myocardial model that considered the patient‐specific morphological variations in LV anatomy to obtain a more precise mapping between segments and the AHA recommended nomenclature. The details are presented in sections II‐IV. In section II, material and methods are introduced, and the experimental results are described in detail in section III. Finally, the discussion and conclusion of our approach are reported in sections IV and V.In our method, short‐axis alignment was performed first after which the LV volume was segmented by seeded region growing method and modeled by finding appropriate control points to represent the inner and outer boundaries of the segmented LV volume. The patient‐specific, 17‐myocardial segments were modeled by delineating the myocardial septum boundaries using the anterior and posterior interventricular grooves. And these boundaries were projected onto the bull's‐eye map. The area of each segment on the bull's‐eye map was measured and the ability of the segmental area to differentiate between normal controls and severe aortic stenosis (AS) patients was evaluated. The short‐axis view shows cross‐sections of the LV that are useful for volumetric measurements. This view was chosen so that the series of slices would be perpendicular to the long axis of the LV that transects the apex and the center of the mitral valve plane.The LV volume segmentation was performed using a thresholding method. From the three seed points , a seeded region growing method was performed to search for 3D connected regions. The SP1 was the center point between the apex and endo‐apex. The SP2 was the center of the long axis that was the center point between the apex and the center of the mitral valve. It was used for detecting the largest connected component that represented the chamber volume of the LV The SP3 was the center of the mitral valve. It was used for the upper boundary of the LV, whereas the apex point was used for the lower boundary. After selecting the seed points, we searched for the largest connected component that represented the LV volume with a specific size by moving from the bottom slice to the top slice.The inner and outer boundaries of the LV  were fitted to the surface by two radiographers with more than five years of experience each. To reduce the manual burden and improve reliability, our quantitative cardiac analysis software platform provided an initial surface contour for each slice. It was modeled using a closed spline curve, consisted of 10 control points and the initial shape was a circle. The position of each control point was calculated from the minimum and maximum boundaries of the generated connected component on the axial view. Two experts modified the initially obtained surface contours, and a cardiac radiologist with more than 10 years of experience confirmed the LV surface contour and its validity.An LV volume mask was generated from the LV surface contour. In theory, this mask could include some part of the aortic root. Therefore, we removed the aortic root from the LV volume by using a thresholding method and basic morphological operation.The segmented LV volume was divided into newly defined patient‐specific 17 myocardial segments. The conventional model divided the myocardium into six segments of 60° each on the basal and midcavity slices in The bull's‐eye map is a quantitative polar representation of LV volume.. Figures2) and it is easy to map between each segment and the numbers at a glance.t‐tests and a diagnostic classification test.To validate the usability of the patient‐specific, 17‐segment myocardial model, 2D quantitative parameters were evaluated from two 17‐segment models on the bull's‐eye map and the 3D parameters were evaluated from volume data. We evaluated whether these parameters could differentiate between normal controls and severe AS patients on the basis of the clinical knowledge that the LV response to aortic stenosis includes LV remodeling.t‐test to evaluate the independence of quantitative parameters from two groups using the area of each segment and a diagnostic classification test to evaluate whether these parameters could differentiate between normal controls and severe AS patients using the maximum likelihood that was estimated from the area of each segment. The proposed method required a manual adjustment to divide the segmented LV volume into the patient‐specific 17 myocardial segments. Therefore, we compared interoperator and intraoperator variability for this procedure using data from 10 randomly selected patients.A retrospective study was performed to validate our patient‐specific, 17‐segment myocardial model. Thus, we used already clinically differentiated groups including AS patients and normal controls that had different anatomic variation. In total, 179 patients underwent electrocardiogram‐gated volumetric cardiac CT scans in the Department of Radiology, Asan Medical Center, South Korea; 144 patients had severe AS and 35 patients had a normal cardiac anatomy. The CT scans were obtained by a second‐generation, dual‐source CT scanner  with a smooth kernel (B26f) and 0.64‐mm slice thickness. The conventional and patient‐specific 17‐segment models were semiautomatically modeled, as described in the Materials and Methods sections A to D. The thickness and mass of each segment in the 3D model and the area of each segment on the bull's‐eye map was quantitatively assessed considering the morphological boundaries. In‐house software was used to measure these parameters. We performed paired p<0.001) between severe AS patients and normal controls. In the case of the 2D parameters, the two models were completely different. Most segments of the conventional model, except segment 3 (p=0.035), showed no differences (p>0.073) between the two groups. However, the parameters of all segments of the proposed model were significantly different (p<0.011).We evaluated the ability of the 3D and 2D parameters of the two 17‐segment models to differentiate between normal controls and severe AS patients. The differences between the two 17‐segment models were described in the Materials & Methods section C above. The evaluation results are shown in p<0.011) may be equivalent to those of 3D segment analysis  for differentiating the two groups.The evaluation results in 0.59±0.19) was more than twice that of the conventional model (0.27±0.06). The AUC for the proposed model (0.69±0.05) was bigger than that of the conventional model (0.60±0.12). Especially, the specificity and AUC for segment 1 of the proposed model (0.71 and 0.72) were more than double that of the conventional model (0.26 and 0.27).p‐value<0.05).The result of intraoperator and interoperator variability test showed the final result could be different, in Our proposed model divided the LV myocardium into 17 segments because the 17‐segment model has used in routine clinical work since it was recommended by AHA and provides the best agreement with the available anatomic data and has the best fit with the methods commonly used in both echocardiography and SPECT nuclear cardiology.The proposed 17‐segment model divided the LV myocardium by considering the position of two interventricular grooves in the circumferential location. These grooves were recommended to separate and identify the septum from the left ventricular anterior and inferior free walls by the AHA.Even though we could have expected this result from the segmental area distribution of the proposed model shown in In clinical purposes, the 2D bull's‐eye map is preferable due to understanding of patient variation at a glance, even though the 3D display would give more accurate and informative patients' information. In addition, medical doctors have used the 2D bull's‐eye map in routine clinical work. Therefore, it is very important to visualize the 2D bull's‐eye map based on the patient‐specific 17‐segment model. The use of patient‐specific segmental areas on the bull's‐eye map could simultaneously increase physician recognition of a patient's specific LV anatomical variations and provide a functional map that includes LV thickness and an intensity map of perfusion, along with other parameters. In addition, we evaluated a correlation between patient weight and our measurements. But we could not find a correspondence between them. However, further study of interrelationships may be helpful in finding a hidden relationship between our measurements and other clinical indexes.The color coding in sensitivity>0.64 and specificity>0.74). The differentiating capability of the proposed model was evaluated by performing a diagnostic classification test using the maximum likelihood that was estimated from the area of each segment . The senThis study had several limitations. First, our method required manual adjustment at each step. Therefore, the final result could be affected by manual delineation of surface contours . An autoall p‐values<0.011). The patient‐specific bull's‐eye map will help to understand the LV morphology at a glance and to minimize the gap between 3D and 2D LV morphologies because it simultaneously represents patient‐specific segment information on the map with visualization of morphological boundaries. It is therefore superior to the conventional 17‐segment model.The conventional myocardial segmentation model has been used to date for quantitative analysis of the LV. However, it does not consider patient‐specific myocardial anatomic variations. We here propose a patient‐specific, 17‐segment myocardial model based on a quantitative cardiac analysis platform. The 2D and 3D quantitative parameters generated by this platform can be used to differentiate between normal controls and severe AS patients. In particular, the differentiating capability of both 2D and 3D parameters of the proposed model demonstrates statistically significant differences . This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea . The authors especially thank Youngsin Kim, Songyi Baek, and Jiyeun Ko for helping with the experimental work.This work is licensed under a Creative Commons Attribution 3.0 Unported License.


Apical hypertrophic cardiomyopathy (AHCM) has been rarely described in the Western world. More recently, improved sensitivity of diagnostic modalities and increased diagnostic awareness have increased detection rates, suggesting that the prevalence outside of Asia may have been previously understated. Hallmark features of AHCM include deeply negative, “giant” T-wave inversions on electrocardiography and a “spade-like” configuration of the left ventricle on ventriculography. We present two cases of AHCM, one in an African-American female and another in a Caucasian male. Apical hypertrophic cardiomyopathy (AHCM) is found in up to 25% of Japanese patients with hypertrophic cardiomyopathy (HCM), but outside of this population, it represents a markedly uncommon morphologic variant of HCM, with most reports suggesting a prevalence between 1% and 3% . The basA 28-year-old African-American woman presented with a several hour history of typical angina. She provided a history of hypertension, hyperlipidemia, metabolic syndrome, and a family history of sudden cardiac death in her 23-year-old brother. Associated symptoms included palpitations, progressive orthopnea, and pedal edema. Vital signs were all within normal limits. Cardiac examination disclosed a prominent S4. Electrocardiography (EKG) revealed left ventricular hypertrophy and deep T-wave inversions in leads V3-V6, but no ST-segment abnormalities . CardiacTransthoracic echocardiography revealed normal left ventricular size and function (ejection fraction 60%), and moderate-to-severe left ventricular hypertrophy. Although the apex was not well visualized, obstructive physiology was noted despite lack of a well-defined gradient.Coronary angiography revealed no significant epicardial coronary disease. Obliteration of the apex in a “spade-like” fashion and elevation of the left ventricular end-diastolic pressure were noted on ventriculography . The diaA 50-year-old Caucasian man with a history of paroxysmal atrial fibrillation, obstructive sleep apnea and a family history of sudden cardiac death in two first-degree relatives presented to the outpatient clinic with palpitations. His initial diagnosis of atrial fibrillation was made 10 years prior and was attributed to excessive caffeine consumption, given that he regained a normal sinus rhythm following cessation of caffeine. At the time of atrial fibrillation diagnosis, transthoracic echocardiogram demonstrated evidence of mild left ventricular hypertrophy. Ten years later, his resting electrocardiogram demonstrated recurrence of rate-controlled atrial fibrillation, left ventricular hypertrophy and 2.5 mm deep T-wave inversion in leads V4-V6. He was placed on an event monitor and was noted to experience 22 beats of non-sustained ventricular tachycardia in addition to periods of atrial fibrillation. He underwent exercise nuclear stress testing according to a standard Bruce protocol, during which he completed 18 s of stage IV prior to experiencing shortness of breath at 100% of his maximal predicted heart rate and concomitant worsening in the degree of T-wave inversions in the inferior and lateral leads . No evidBoth of our patients and their first-degree family members declined any genetic testing. At subsequent 6-month follow-up visits, both patients were asymptomatic and reported adherence to beta-blocker therapy. No inadvertent defibrillator shocks were reported.The apical variant of HCM in which left ventricular wall thickening is confined to the most distal region of the apex has been regarded as a phenotypic expression of non-obstructive HCM largely limited to Japanese patients. Nevertheless, since its original description in the 1970s , 5, seveOur first case highlights the potential for AHCM to manifest early in adulthood, similar to other more commonly seen variants of HCM . Most otThe second case in our series is representative of the more common, older-onset AHCM . Our patEthnically, AHCM accounts for 13-41% of all variants of HCM among Asian individuals, whereas the prevalence among non-Asians is < 5% . HoweverNo definitive guidelines delineate the role for defibrillator implantation in AHCM patients with family histories of sudden cardiac death. Not surprisingly, expert consensus supports the use of implantable defibrillator for primary prevention in select high risk patients, notably those with one of the five following risk factors: a family history of sudden cardiac death, syncope, asymptomatic non-sustained ventricular tachycardia, an abnormal blood pressure response to exercise and a left ventricular wall thickness > 30 mm . Genetic


The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation. Valvular heart disease (VHD) is an important public-health problem with an increasing prevalence along with ageing of the population . ModeratChronic pressure and volume overload caused by severe left-sided VHD results in LV remodeling. Changes in the extracellular matrix with deposition of collagen I and loss of myofibers at a later stage result in myocardial fibrosis, the hallmark of LV remodeling , 6. CardLV remodeling in response to chronic pressure and volume overload caused by VHD is characterized by progressive increase of the interstitial space with increased collagen volume fraction (reactive fibrosis) and eventually apoptosis of myocardial cells which are replaced by firm fibrous tissue (replacement fibrosis or scar). T1 mapping and LGE CMR techniques are currently the most frequently used techniques to directly assess myocardial fibrosis . Although still not implemented in routine clinical practice, the measurement of myocardial ECV in patients with AS has important clinical implications [2) but without LGE (replacement fibrosis) showed significantly higher all-cause mortality and AS-related mortality rates (36 per 1000 patients-year for both) as compared to the patients with normal myocardium  , pressure and volume overload induce growth of cardiomyocytes with addition of new sarcomeres in series and interstitial fibrosis, characterized by increased fibronectin and non-collagen components . SeveralMitral regurgitation (MR) is a heterogeneous disease, broadly classified as organic (primary) or functional (secondary) based on the underlying mechanism. Organic MR is due to intrinsic valvular disease whereas functional MR is caused by regional and/or global LV remodeling without structural abnormalities of the mitral valve . DegenerThese structural changes of the LV myocardium may be associated with subtle functional abnormalities. In 15 patients with chronic moderate and severe MR and preserved LV ejection fraction who underwent CMR with tissue tagging, Maniar et al. demonstrated preserved global longitudinal and circumferential strain but abnormal regional strain values: the septal LV segments exhibited impaired strain whereas the lateral segments showed compensatory hyper-contractility . SimilarTissue characterization and strain imaging with CMR have provided new insights into the pathophysiology of VHD. Current guidelines recommend valve surgery in severe symptomatic VHD or when LV function decreases , 3. HoweThe early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with advanced aortic stenosis (EVOLVED) is the first multicenter randomized controlled clinical trial that will investigate whether the early valve intervention in patients with asymptomatic severe AS and midwall fibrosis on CMR improves patients’ clinical outcomes compared to the standard care (NCT03094143). The results of this study may have an impact on future guidelines and recommendations on treatment of VHD.