Repair of tetralogy of Fallot (ToF) frequently has long-term sequelae of right ventricle (RV) dysfunction, which may also lead to left ventricular (LV) dysfunction due to unfavorable RV coupling. We hypothesized that ToF can lead to adverse left heart remodeling, including LV myocardial extracellular matrix expansion, hallmarks of a cardiomyopathic process.Cardiac magnetic resonance (CMR) was performed at 3.0 Tesla in 109 asymptomatic ToF patients, (age 19.3±12.8 years) after surgical correction (16.6±10.0 years post operation), and 64 age-matched controls. Parameters of LV and left atrial (LA) function and aortic distensibility were obtained from cine CMR. In a subgroup (n=50), T1 mapping was used to determine the myocardial extracellular volume fraction (ECV) as an index of diffuse myocardial fibrosis.Compared to control subjects, ToF patients had a lower LV ejection fraction (EF) , despite a similar RV EF (p=0.34). ToF showed a lower LV mass index, lower LV mass-to-volume ratio, and lower aortic distensibility. LA passive volume and LA total ejection fraction were decreased, and associated with age (p<0.01), suggesting an early onset of diastolic dysfunction. ECV was elevated in ToF (0.32±0.05 versus 0.26±0.01 in controls (p<0.01), more so in females (p<0.05), and was inversely associated with LV mass index (p<0.05).During long-term follow-up after repair of ToF, asymptomatic patients show alterations in LV geometry, function, tissue structure, and aortic distensibility. These findings indicate an early adverse cardiovascular phenotype and underscore the need for life-long follow-ups.This work was supported by a Postdoctoral Fellowship grant from Coordination of Improvement of Higher Education Personnel (CAPES), Brazil.


There is limited evidence regarding intra-observer and inter-observer variations in echocardiographic measurements of diastolic function. This study aimed to assess this reproducibly within a population-based cohort study.th visit participants of the STANISLAS Cohort . This 4th examination systematically included M-mode, 2-dimensional, DTI and pulsed-wave Doppler echocardiograms. Reproducibility of variables was studied by intra-class correlation coefficients (ICC) and Bland Altman plots.Sixty subjects in sinus rhythm were randomly selected among 42) and non-smoking (87%) with a quarter of the participants having self-declared hypertension or treated with anti-hypertensive medication(s). Intra-observer ICC were > 0.90 for all analyzed parameters except for left ventricular ejection fraction (LVEF) which was 0.89 (0.81–0.93). The mean relative intra-observer differences were small and limits of agreement of relative differences were narrow for all considered parameters (<5% and <15% respectively). Inter-observer ICC were > 0.90 for all analyzed parameters except for LVEF (ICC = 0.87) and both mitral and pulmonary A wave duration (0.83 and 0.73 respectively). The mean relative inter-observer differences were <5% for all parameters except for pulmonary A wave duration (mean difference = 6.5%). Limits of agreement of relative differences were narrow (<15%), except for mitral A wave duration and velocity (both <20%) as well as left ventricular mass and pulmonary A wave duration (both <30%). Intra-observer agreements with regard to the presence and severity of diastolic dysfunction were excellent (Kappa = 0.93 (0.83–1.00) and 0.88 (0.75–0.99), respectively).Our population was on average middle-aged (50 ± 14y), overweight (BMI = 26 ± 6kg/mIn this validation study within the STANISLAS cohort, diastolic function echocardiographic parameters were found to be highly reproducible. Diastolic dysfunction consequently appears as a highly effective clinical and research tool. Heart failure (HF) with preserved left ventricular (LV) ejection fraction (EF) is a progressive disorder characterized by impaired LV relaxation, increased LV stiffness, increased interstitial deposition of collagen and modified extracellular matrix proteins. HF with preserved LVEF (HFPEF) is frequently referred to as diastolic heart failure because of the presence of diastolic LV dysfunction resulting from slow LV relaxation and increased LV stiffness . BecauseThe gold standard for assessing diastolic function remains pressure-volume relationship. However, this invasive approach is never used in clinical practice. An extensive non-invasive assessment of diastolic function is now possible, and its clinical evaluation is mostly based on echocardiographic parameters . Indeed,The value of a given parameter is based on its ability and reproducibility to correctly predict a clinical entity. Therefore, each parameter of diastolic function should be obtained in a standardized and reliable manner.Verifying the reliability of each parameter of diastolic function is a crucial aspect in clinical practice because it assists clinicians in establishing the diagnosis of HFPEF and decision-making especially in situations of discordant echocardiographic parameters. In epidemiology, accuracy of a measurement process is defined as the degree to which a measurement represents the true value of the parameter being measured. Reproducibility refers to the capacity to produce the same result on each occasion under identical conditions . A measuRecently, an array of HF biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF, namely myocardial insult, inflammation and remodeling. The assessment of a new biomarker should be made on a wide range of patients and in typical conditions of its intended use. The diagnostic methods used to detect diastolic HF should thus be contemporary, rigorous, standardized and fair. Consequently, we endeavored to assess LV diastolic function using an accurate measurement process.The present study was aimed to validate a standardized process of echocardiographic assessment of diastolic function in a population-based study by analyzing both intra-observer and inter-observer reproducibility of all parameters of diastolic function.The STANISLAS Cohort is a single-center familial longitudinal cohort comprised of 1006 families (4295 subjects) from the Nancy region recruited in 1993–1995 at the Centre for Preventive Medicine. This cohort was established with the primary objective of investigating gene-gene and gene-environment interactions in the field of cardiovascular diseases. The families were deemed healthy, free of declared acute and/or chronic illness, in order to assess the effect of genetics on the variability of intermediate phenotypes on the transition toward pathology.th examination at our department. M-mode, 2-dimensional, DTI and pulsed-wave Doppler echocardiograms were routinely performed at the 4th examination. For the present study, 60 subjects in sinus rhythm were randomly selected from the STANISLAS Cohort study.From 2011 to 2014, 1200 survivors of the original cohort underwent their 4The research protocol was approved by local Ethics Committee (Comité de Protection des Personnes Est III—Nancy—France) and all study participants gave a written informed consent to participate. The informed written consent was previously approved by the local Ethics Committee.Examinations were performed by an experienced echocardiographer in the left lateral decubitus position with a commercially available standard ultrasound scanner  using a 2.5 MHz phased-array transducer (M5S). The echo/Doppler examination included parasternal long- and short axis views and three standard apical views. For each view, at least three consecutive cardiac cycles were recorded during quiet respiration.From the three apical views, separate M-mode and color tissue Doppler acquisitions were recorded. The Doppler pulse repetition frequency was 1 kHz. Pulsed-wave (PW) Doppler was performed in the apical 4-chamber view to obtain mitral inflow velocities to assess LV filling. Recording for isovolumic relaxation time measurement was obtained by simultaneous recording of the aortic and mitral flows. PW Doppler Tissue Imaging (DTI) was performed in the apical views to acquire mitral annular velocities. The sample volume was positioned at 1 cm of the septal and lateral insertion sites of the mitral leaflets and adjusted as necessary  to cover the longitudinal excursion of the mitral annulus in both systole and diastole. Pulmonary venous flow velocities were recorded into the right upper pulmonary vein from the apical 4-chamber view. Color flow imaging was used for the proper location of the sample volume and the 2-mm sample volume was placed 5 mm into the pulmonary vein for optimal recording of the spectral waveforms.All acquired images and media were stored on a secured network server as digital clips, using a unique identification number and analyzed on a dedicated workstation .Two experienced physician echocardiographers (Z.F. and O.H.), blinded to each other and to the demographic parameters, performed a separate complete analysis of diastolic function of the 60 participants. The first physician echocardiographer (Z.F.) re-analyzed the entire data set of all 60 study patients a second time. The re-analyses were performed in random order after a period of 4 weeks. The first reading of the first analyzer (Z.F.) was considered for the statistical analysis of inter-observer variability.Intra-analyzer reproducibility was defined as the reproducibility calculated by one of the echocardiographer's re-analysis of his own recordings (Z.F.). Inter-analyzer reproducibility was defined as the reproducibility calculated by the two echocardiographers’ analyses of the same set of recordings.LV mass: LV mass was measured from 2-dimensional (2D) echocardiography, using the recently published guidelines of the American Society of Echocardiography. We measured the septal wall thickness (SWT), posterior wall thickness (PWT) and LV internal diastolic diameter (LVID) from the parasternal 2D long axis view. These measurements were subsequently used in the cube-function formula for ASE guidelines to calculate LV mass .LA Volume: The measurement of left atrial (LA) volume was obtained from the biplane method of disks (modified Simpson’s rule) using apical 4-chamber (A4C) and apical 2-chamber (A2C) views at ventricular end systole .Mitral Inflow: The following parameters were studied: peak early filling (E-wave) and late diastolic filling (A-wave) velocities, E/A ratio, deceleration time (DT) of early filling velocity and mitral A-wave duration obtained at the tip of the mitral valve leaflets.Pulmonary Venous Flow: Measurements included peak systolic (S) velocity, peak anterograde diastolic (D) velocity, the peak reversal A-wave (Ar) velocity in late diastole and the duration of Ar velocity,Tissue Doppler Annular Early and Late Diastolic Velocities: Measurements included systolic (S), early diastolic (Ea) and late diastolic velocity (Aa) of the septal and lateral mitral annulus .Assessment of left ventricular diastolic dysfunction was made according to the recommendations of the American Society of Echocardiography and the Committee of the European Association of Echocardiography  using thLVEF was calculated using the biplane Simpson’s method.The reproducibility of continuous variables is expressed by the intra-class correlation coefficients (ICC). As all analyzed parameters constituted continuous variables, the inter-observer and intra-observer agreements were estimated using the ICC. Agreement was classified as poor (ICC = < 0.40), fair to good (ICC = 0.40–0.75) or excellent (ICC > 0.75).For descriptive purposes, the Bland Altman plots report the means of the ratings for each patient by two raters vs. the differences in ratings. Mean absolute error was calculated as the mean of the absolute difference between the two sets of observations . The meaP values < 0.05 were considered statistically significant. All analyses were performed using SAS version 9.3  and SPSS 21 .Overall, our study population was middle-aged, overweight and non-smoking (13%), with a quarter of the participants having self-declared hypertension or being on anti-hypertensive medication .The intra-observer ICC coefficients were >0.90 for all analyzed parameters except for LVEF which was 0.89 (0.81–0.93) .The mean relative intra-observer differences were <5% for all parameters .The limiThe inter-observer ICC coefficients were >0.90 for most analyzed parameters . SlightlAs expected, most limits of agreement were larger for inter-observer comparisons than that observed for intra-observer comparisons .The meanIntra-observer agreement with regard to both the presence of diastolic dysfunction and the severity of diastolic dysfunction was excellent (respectively Kappa = 0.93 (0.83–1.00) and 0.88 (0.75–0.99) . Inter-oIn the present study, we analyzed the reproducibility of all previously validated Doppler indices of diastolic function. The main finding of this study was that both inter- and intra-observer reproducibility was excellent for most diastolic function parameters with limits of agreement sufficiently narrow to conclude that the fluctuation in measurements of diastolic function is unlikely to have a noteworthy impact on diastolic function classification. We also report excellent inter- and intra-observer agreements with regard to diastolic dysfunction identification and grading. Overall, these results thus qualify the STANISLAS cohort for further research in the field of diastolic function, including the validation of biomarkers to predict and classify echocardiographic diastolic function.While prior investigations have assessed the magnitude of variability parameters of diastolic function, these measurements were performed separately and in limited numbers of normal subjects in clinical setting ,10–13.ThThe intra-observer reproducibility for LV systolic function observed in the present study ICC = 0.89) was globally better than that previously reported. In the study of Palmieri et al., a poor reliability was observed for measurements of LV systolic function (ICC = 0.65). In cont9 was gloThe present study also yielded superior results than previous studies regarding inter-observer reproducibility of systolic and diastolic function as well as LV mass measurements. Indeed, in the study of Otterstad et al. , there wLV Linear Dimensions and Wall Thickness are used for virtually all clinical trials that incorporate echocardiography. Linear dimensions are obtainable from correctly-aligned 2D and M-mode images. M-mode recordings provide better temporal resolution for accurate timing of motion of cardiac walls and valves, whereas 2D provides better spatial orientation. With respect to LV mass, Valdez et al.  found stIn our study, overall inter-observer agreement in the assessment of diastolic dysfunction classification was better than the results of a multicenter study reported by Unzek et al.–21 18–2–218–21. The present study revealed a low inter-observer correlation for pulmonary A wave duration with a relatively weak inter-observer agreement ICC = 0.73) and mean relative inter-observer differences >5%. This result can be explained by the difficulty in the acquisition of this parameter. Indeed, one of the important limitations in interpreting pulmonary venous flow is the difficulty in obtaining high-quality recordings suitable for measurements. This is especially true for pulmonary A wave duration because of low-velocity wall motion artifacts created by atrial contraction that obscure the pulmonary flow velocity signal. Importantly, this variable involved in the determination of filling pressures is not present in the ASE/ESC algorithm of diastolic dysfunction [ and meanMost previously-conducted studies varied considerably in terms of study design and analysis methods, making direct comparison difficult –21. TherOur analysis results compared favorably with other studies. These good results are explained by the design of our protocol based on reanalysis of the same recorded images collected previously by trained operators with a high-resolution system. According to Otterstad et al. , the majThe successful application of echocardiography in clinical heart failure trials depends on careful attention to quality control, including echocardiographic acquisition and interpretation harmonization by an experienced and competent core laboratory. The present study thus focused on specific echocardiographic parameters to obtain positive evidence of abnormal LV relaxation, filling, diastolic distensibility and diastolic stiffness, in addition to assessing the reliability of specific parameters needed to classify the patient according to the diagnostic flowchart of the Echocardiography Associations of the European Society of Cardiology.http://www.homage-hf.eu/), a biomarker validation  for the prediction of diastolic dysfunction and presymptomatic heart failure. Obviously, such a validation can solely be obtained for a reproducible echo assessment of diastolic function.Natriuretic peptides and echocardiography are the main tools to detect HF. In the setting of HF with preserved LVEF, echocardiography is of key importance, especially in older patients in whom the use of natriuretic peptides has some limitations. However, access to echocardiography is sometimes difficult and/or long and further compounded by the fact that echocardiographic measurements can show high individual variability in addition to varying day to day in the same patient with changes in preload, afterload and heart rate. We are currently conducting, within the HOMAGE FP7 program (In the current validation study, all of the echocardiographic parameters assessing diastolic function were found to be highly reproducible in the STANISLAS cohort. Given this high reproducibility of diastolic function assessment, and more specifically in this population-based study, we are thus confident of being able to validate a number of new biomarkers to predict diastolic dysfunction.In addition, the high reproducibility of diastolic function parameters combined with the observed good agreement relative to diastolic dysfunction identification and grading has important practical clinical implications. We provide strong evidence to support that echocardiographic assessment of diastolic function is a reliable and trustworthy clinical tool in terms of metronomic properties.The results of our study are based on patients with normal sinus rhythm, which may limit the generalizability of our findings to subjects in atrial fibrillation. Further studies are warranted to assess the reproducibility of diastolic dysfunction grading in patients with atrial fibrillation.In the present study, we have validated an operating process for echocardiographic image analysis and quality control measurement for the assessment of diastolic function in patients with sinus rhythm of the STANISLAS cohort study. The excellent results observed in our analysis compared with other studies are explained by the design of our protocol and the single-center nature of our study. This excellent reproducibility will enable the validation of new biomarkers within EU- and French-funded research programs. In addition, in light of these results, diastolic dysfunction echocardiographic assessment thus appears as a highly reliable clinical and research tool.


We report atrio-ventricular cross talk in a patient with a dual chamber ICD leading to ventricular pacing inhibition. This was observed in an ICD without the ventricular safety pace option, which normally is a sufficient protection against this phenomenon. Cross talk could be prevented effectively by reprogramming ventricular sensitivity to a less sensitive setting. Atrioventricular (A-V) cross-talk resulting in ventricular inhibition is a known phenomenon since the introduction of devices with dual-chamber pacing and ventricular sensing capabilities . Cross-tAn 83-year-old male patient had a DDD pacemaker (Medtronic Kappa 733) implanted in 1995, because of complete atrioventricular (AV) block. Due to progressive heart failure, the pacemaker was upgraded in 2004 to an ICD with cardiac resynchronization therapy . For this purpose a Guidant 0138 ICD shock lead was implanted in the right ventricle and a Medtronic Attain 4194 in a posterolateral branch of the coronary sinus for left ventricular pacing. The preexisting Medtronic 4524 atrial lead was used for atrial pacing and sensing, and the bipolar right ventricular lead was abandoned. A hospital admission because of ventricular tachycardias showed successful termination of these tachycardias by ICD shock therapy. Except shock therapy, the patient complained of dizzy spells, which at that time were attributed only to the ventricular tachycardias. However, at the time of device interrogation, the ECG showed intermittent ventricular inhibition. Inhibition did not occur during atrial sensing, which is a strong indicator of cross-talk sensing. A Holter recording performed 24 hours prior to the device checkup revealed several periods of asystole with duration up to 7.4 seconds as a consequence of cross-talk sensing . The cheThe pacing parameters were DDD 65 till 110 beats/min and dynamic AV delay 160 ms/100 ms pacing output in atrial and RV 2.6 V at 0.06 ms, and LV 3.0 V at 0.5 ms, the RV-blank after A-pace was 65 ms, and the RV sensitivity was set to nominal.Neither prolongation of the ventricular blanking period to 85 ms nor decreasing atrial output to 1.0 V at 0.5 ms could eliminate cross-talk sensing . FinallyCross-talk sensing is a rare phenomenon, which can be life-threatening or symptomatic if it results in ventricular inhibition, as illustrated in this case. In patients with complete AV block or in absence of underlying rhythm, extra attention is warranted. There are several factors promoting cross-talk sensing. Increase of atrial output (amplitude and pulse width), more sensitive setting of the ventricular channel, unipolar electrode configuration of the atrial and ventricular channel, and increasing pacing rates are known causes of cross-talk sensing. Exceptional is cross-talk sensing by increase of ventricular output . When cross-talk sensing cannot be eliminated by adaptation of one or more of the here a forementioned parameters or by lengthening of the ventricular blanking period, ventricular inhibition can be prevented by a safety feature called “Ventricular Safety Pacing (VSP).” This method uses a brief sensing period  after the ventricular blanking period starting at the atrial stimulus . Any eleUnfortunately the current device was not equipped with the feature of VSP, and ventricular inhibition could only be prevented by reduction of the ventricular sensitivity. The latter option is not the first choice in patients with ICDs, because reduction of sensitivity may result in undersensing during ventricular arrhythmias.


Although it is known that Anderson-Fabry Disease (AFD) can mimic the morphologic manifestations of hypertrophic cardiomyopathy (HCM) on echocardiography, there is a lack of cardiovascular magnetic resonance (CMR) literature on this. There is limited information in the published literature on the distribution of myocardial fibrosis in patients with AFD, with scar reported principally in the basal inferolateral midwall.All patients with confirmed AFD undergoing CMR at our center were included. Left ventricular (LV) volumes, wall thicknesses and scar were analyzed offline. Patients were categorized into 4 groups: 1) no wall thickening; 2) concentric hypertrophy; 3) asymmetric septal hypertrophy (ASH); and 4) apical hypertrophy. Charts were reviewed for clinical information.n = 5) had greater maximum wall thickness, total LV scar, apical scar and mid-ventricular scar than those with concentric hypertrophy . Patients with elevated LVMI had more overall arrhythmia (p = 0.007) more ventricular arrhythmia (p = 0.007) and sustained ventricular tachycardia (p = 0.008).Thirty-nine patients were included . Almost half (17/39) had concentric wall thickening. Almost half (17/39) had pathologic LV scar; three quarters of these (13/17) had typical inferolateral midwall scar. A quarter (9/39) had both concentric wall thickening and typical inferolateral scar. A subgroup with ASH and apical hypertrophy  contains supplementary material, which is available to authorized users. X-linked mutations in the α-galactosidase gene cause Anderson Fabry disease (AFD), a lysosomal storage disorder . Althoug>30s). Clinical data were abstracted from the charts by a board-certified cardiologist.Institutional research and ethics board approval was obtained for this retrospective study (REB#: 12-5646-AE) from the University Health Network Research and Ethics Board, and the requirement to obtain individual patient consent was waived. Patients with confirmed AFD, identified through our metabolic genetic disease clinic between 1/1/2000 and 31/12/2013, who had CMR (with LGE sequences) at our institution, were included in this study. We included only patients with disease-causing AFD mutation or positive leukocyte alpha galactosidase A activity test confirming a diagnosis of AFD. Exclusion criteria were age <18 at CMR acquisition, more than mild aortic stenosis, disease-causing HCM mutations and LGE due to myocardial infarction. Arrhythmia was defined as documented ventricular arrhythmia or atrial fibrillation. Ventricular arrhythmia was defined as documented non-sustained ventricular tachycardia (>6 beats at a minimum of 120 beats/min) and/or an episode (or episodes) of sustained ventricular tachycardia  or Signa HDx Twin Speed  scanner or a 3.0-T Magnetom Verio scanner . CMR scanners were equipped with either a 32-element or an eight-element cardiac array coil. Typical steady-state free precession parameters were as follows: spatial resolution of 1.3–1.5 x 1.3–1.5 mm, section thickness of 6–10 mm and gap of 0–2 mm; and temporal resolution of 35–50 msec. LGE was performed with either segmented gradient-recalled echo or single-shot steady-state free precession inversion-recovery sequences 8–10 min after intravenous administration of 0.2 mmol/kg gadobutrol .>13 mm. The population was divided into those with and without wall thickening.All studies were reviewed and analyzed by a single experienced Level III CMR reader using commercially available CMR post-processing software . The CMR reader was blinded to all clinical data. Maximum end-diastolic wall thickness (EDWTmax) was measured manually from cardiac short-axis . Wall thickening was considered to be present if there was an EDWTmax of Semi-automated (modified centerline technique) average wall thickness measurements and volumes for each myocardial segment and LV mass were produced by the software based on a 16-segment model . Semi-au>1.3) [We divided the cohort into 4 subgroups based on their morphological phenotypes; 1) those without wall thickening; 2) those with apical predominant thickening; 3) those with asymmetric septal hypertrophy (ASH) (SLR >1.3)  and 4) t2 for males and above 81 g/m2 for females when indexed to body surface area (LVMI) [Left ventricular mass was quantified including LV papillary muscles and trabeculae and was considered elevated when above 85 g/ma (LVMI) . LV papia (LVMI) .Late gadolinium enhancement (LGE) sequences acquired in conventional cardiac short-axis and 4, 3 and 2-chamber orientations as well as a stack of LGE images in a 4-chamber orientation  were assU-test. Spearman correlation coefficient was utilized to assess correlation between continuous variables. Intraobserver and interobserver agreement was assessed by correlation coefficient.Continuous variables were presented as median (interquartile range). Categorical variables were analyzed with Fisher’s exact test. Group comparisons were analyzed using the Mann-Whitney p = 0.025) and older . The septal to lateral wall ratio ranged from 0.76 to 1.61 , Fig. p = 0.066)  had evidence of LGE  as well as between total LV scar and LVMI  had more total LV scar, apical LV scar and mid ventricular LV scar than patients with concentric wall thickening (n = 17)  Table .p = 0.141) and, 0.98 for interobserver agreement  with minimal bias .Interobserver agreement was assessed utilizing the 17 cases with pathological scar. Concordance correlation coefficient was 0.93 for intraobserver agreement  with minimal bias  had both extracardiac and cardiac involvement (‘classic variant’); 11 patients (28 %) had only extracardiac involvement; and 4 patients (10 %) were carriers. There were no patients in our cohort with only cardiac manifestations of AFD (‘cardiac variant’). The majority of ‘classic variant’ patients had wall thickening (92 %), pathological LGE (71 %), typical inferolateral scar (54 %), and concentric wall thickening (71 %). All patients with non-concentric wall thickening had ‘classic variant’ AFD.p = 0.007). Patients with arrhythmia (n = 10) had greater LVMI than those without arrhythmia (n = 31), . Patients with ventricular arrhythmia (n = 5) had significantly greater LVMI and LV papillary muscle mass (Table n = 2) had greater LVMI, papillary mass and trabecular and papillary muscle volume . Elevated LVMI was associated with ventricular arrhythmia  and sustained ventricular tachycardia  respectively. There was a significant association between elevated trabecular and papillary muscle volume and all arrhythmia (p < 0.001), ventricular arrhythmia (p = 0.010) and sustained ventricular tachycardia (p = 0.013). There was no significant association between LA volume and atrial fibrillation.There was more arrhythmia in patients with elevated LVMI (8/16 with elevated LVMI vs. 2/23 with normal LVMI, Previous CMR literature on AFD has focused on scar patterns in AFD. Although CMR, with its high spatial resolution, is ideally suited to assess patterns of LV wall thickening , to our Published CMR findings to date have emphasized the typical pattern of myocardial scar seen in AFD , 25–27 . HoweverIn addition, we found 5 patients with midwall scar at fibrous-muscular interfaces including valve annuli/LV wall and chordae tendinae/papillary muscle heads respectively, which to our knowledge has not been described in the imaging literature to date. The presence of papillary scar is unsurprising given the prior reports of enlarged papillary muscles and disproportionate contribution of trabeculae and papillary muscles to total LV mass in AFD , 31. We Our analysis was limited by the small sample size, but this is to be expected given of the rarity of the disease, estimated at between 1 in 7000–8000 live births . For theWhile we found that patients with both ventricular arrhythmia of any duration had more LV scar, our sample size was too small to prove a definite association. Lastly, multivariable logistic regression was not possible due to the small sample size. As non-concentric patterns of wall thickening were associated with increased LV mass and scar, larger multicenter long term outcome studies focusing on AFD patients with these patterns of hypertrophy and apical predominant scar may be helpful in teasing out other risk factors for ventricular arrhythmia.Our cohort demonstrates that Anderson-Fabry disease has a number of different phenotypic expressions both in extent and location of hypertrophy and pattern of scar. There is consequently a direct overlap between the AFD phenotype and HCM phenotype. It is therefore unsafe to rely on imaging appearances alone when trying to exclude or make the diagnosis of AFD, and genetic testing is still indicated where there is still a reasonable degree of clinical suspicion. Some centers, including ours, offer AFD screening to all potential HCM patients because of the existence of AFD variants with only cardiac manifestations. Concentric thickening and inferolateral mid-myocardial scar are the most common manifestations of AFD, but the spectrum includes cases morphologically identical to apical and ASH subtypes of HCM and these have more apical and mid-ventricular LV scar than cases with concentric thickening. Further research into differences in clinical outcomes between concentric and non-concentric morphologic subtypes is warranted in larger cohorts. Patients with elevated indexed left ventricular mass in our cohort had a greater incidence of ventricular arrhythmia. Further research collaborations should focus on the potential link between LV mass, LV scar burden and distribution, and ventricular arrhythmia in Anderson Fabry Disease.


Renal Denervation (RDN) is a novel therapy for patients with resistant hypertension. Its cardiac effects at follow-up are currently unknown. On the other hand, T1 mapping permits the assessment of myocardial extracellular volume (ECV), a parameter proposed to quantify diffuse myocardial fibrosis and independently associated with mortality and hard cardiovascular events. Our aim was to study the effects of RDN on ECV at 6-month follow-up.14 patients with resistant hypertension undergoing RD (RD group) and 4 resistant hypertensive patients not undergoing RD (control group) were prospectively included. A 1.5T cardiac MR including T1 mapping pre- and post-contrast was performed before the RD procedure and at 6-month follow-up in both groups. Blood hematocrit was determined at both time points. Images were post-processed using commercial software , and whole left ventricle (LV) ECV and septal ECV at baseline and at 6-month follow-up were quantified as follows: ECV = (1-hematocrit) * λ, where λ = (1/T1 myocardium post-contrast - 1/T1 myocardium pre-contrast)/(1/T1 blood post-contrast - 1/T1 blood pre-contrast).No significant differences in whole LV ECV or septal ECV were observed between baseline and 6-month follow-up in the RD group. In contrast, control patients presented an increase in whole LV ECV and septal ECV at 6-month follow-up which did not reach statistical significance . When the results were expressed as a % of change versus baseline, the % change of ECV septal was significantly different between the RDN and control groups (-5.4 ± 14.4 (-3.8) vs 22.9 ± 4.2 (21.5), respectively, p = 0.02; results expressed as mean ± SD (median)) (Figure Extracellular space could increase at follow-up in non-RDN patients, potentially reflecting a progressive increase in myocardial fibrosis content. This effect is not observed in RDN patients, suggesting a beneficial effect of RDN in delaying this fibrotic progression. Our results are preliminary and need to be confirmed in a larger population.None.


There is also evidence that a left ventricular (LV) lead localized to the latest contracting LV site predicts superior response, compared to an LV lead localized remotely from the latest contracting LV site.Despite marked benefits in many heart failure patients, a considerable proportion of patients treated with cardiac resynchronization therapy (CRT) fail to respond appropriately. Recently, a “U-shaped” . We assessed the final LV lead position on post-procedural fluoroscopic images to determine whether the lead was positioned concordant to or remote from the latest contracting LV site. CRT response was defined as a ≥ 15 % reduction in ESV on a 6 month follow-up echocardiogram.We prospectively evaluated patients undergoing CRT with pre-procedural CMR to determine the presence of type II pattern and an LV lead concordant to the latest contracting site (T2CL) had a response rate of 92 %, compared to a response rate of 33 % for those without T2CL (p = 0.003). T2CL was the only independent predictor of response on multivariate analysis . T2CL resulted in significant incremental improvement in prediction of echocardiographic response .The study included 33 patients meeting conventional indications for CRT with a mean New York Heart Association class of 2.8 ± 0.4 and mean LV ejection fraction of 28 ± 9 %. Overall, 55 % of patients were echocardiographic responders by ESV criteria. Patients with both a type II wall motion pattern on CMR and a concordant LV lead predicts superior CRT response. Improving patient selection by evaluating wall motion pattern and targeting LV lead placement may ultimately improve the response rate to CRT.The presence of a  Cardiac resynchronization therapy (CRT) improves morbidity and mortality in many heart failure patients, yet 1 in 3 patients fail to respond , and curtype II) LV wall motion pattern, suggestive of electrical conduction block, can be demonstrated with cardiovascular magnetic resonance (CMR), and has been associated with a superior CRT response compared to a more homogenous (type I) pattern [A “U-shaped” , QRS duration > 120 ms, and New York Heart Association functional class II or III symptoms despite optimal medical therapy. Patients were enrolled only if they would be able to follow up 6 months after the CRT procedure and if they had no known contraindications to CMR. The Emory University institutional review board approved the study and all patients gave written informed consent prior to enrollment.A favorable electrocardiogram (ECG) was defined as true LBBB morphology and QRS duration > 150 ms. True LBBB morphology was classified as a QS or rS complex in V1 and/or V2; monophasic R wave in leads I, aVL, V5, and V6; and mid QRS notching or slurring in at least two of the following leads: I, aVL, V1, V2, V5, or V6. Non-favorable ECGs were those that demonstrated an atypical LBBB, an intraventricular conduction delay not satisfying criteria for true LBBB, or a QRS duration < 150 ms. Given that significant intraventricular conduction delay may exist in the presence of right bundle branch block , 18, patPatients underwent two-dimensional transthoracic echocardiography at baseline and at 6 month follow-up. The echocardiographic studies were performed on a General Electric Vivid 7 . LV end-systolic volume (ESV), end-diastolic volume, and EF were assessed by Simpson’s modified biplane method of discs using the apical four-chamber and apical two-chamber views. All echocardiograms were reviewed by a board-certified reader blinded to baseline and follow-up status.CMR was performed on a 1.5 T Siemens Avanto scanner  with a 5-element phased array coil and ECG triggering. Steady-state free precession (SSFP) short-axis images were acquired parallel to the mitral valve plane to cover the entire length of the LV (8 mm slices with no slice gap). Two-, three-, and four-chamber cine images were also acquired. Late gadolinium enhancement (LGE) CMR was performed with a phase-sensitive inversion recovery sequence 10–15 minutes after the administration of 0.1 mmol/kg MultiHance . LGE images were acquired in the basal, mid, and apical short axis, as well as the two-, three-, and four-chamber views. Significant scar was defined as enhancement in > 15 % of LV myocardium .Endocardial borders were traced on each frame of the short-axis cine images and radial displacement curves were generated as previously described . Brieflytype I if the wave front proceeded homogenously from the septum to the LV free wall (no adjacent early and late segments) and type II if the wave front was heterogeneous with evidence of an inferred line of block  and then mapped to a modified American Heart Association 17-segment model  latest contracting segment.The number of discrete myocardial sites sampled per segment ranged from 50–100, depending on the number of short axis slices obtained (i.e. the LV length) and the apical versus mid or basal position. The latest contracting site was defined as latest single site to reach maximum radial displacement. The segment containing this site was defined as the The implanting electrophysiologist had no knowledge of the CMR derived wall motion patterns prior to implantation. All CRT devices were implanted using standard procedure. Briefly, central venous access was gained via either the subclavian vein or cephalic vein cut-down. Biplane balloon catheter coronary venography defined coronary venous anatomy in the 30° right-anterior-oblique and 30° left-anterior-oblique views. A suitable anterolateral, lateral, or posterolateral coronary vein was selected based solely on anatomic characteristics; the CMR data was not used to guide this decision.concordant if placed in a viable segment within 1 segment of the latest contracting segment, and remote if placed more than 1 segment from the latest contracting segment. If the LV lead was placed in a non-viable segment with > 50 % transmural LGE, lead position was considered remote.Final LV lead position was determined by biplane fluoroscopy and comparison to baseline venous anatomy by coronary venography. The right anterior oblique image defined long-axis position, while the left anterior oblique image defined short-axis position Fig. . Using ttype II pattern and concordant lead (T2CL) to those without both of these findings (i.e. type I pattern and/or remote leads).The primary outcome was positive echocardiographic response to CRT, defined as reverse LV remodeling with a reduction in ESV by ≥ 15 % at 6 months. We compared response in patients with both a t-test  or the Mann–Whitney U test . Predictors of CRT response were analyzed by univariate binary logistic regression analysis. Independent predictors were analyzed by multivariate binary logistic regression analysis in a model including traditional variables associated with CRT response . A 1000 sample bootstrapping analysis was done to assess internal validity of the multivariate model using SPSS. In an exploratory analysis, novel imaging variables  were added to the multivariate model to evaluate for an additional effect. The incremental benefit of T2CL was assessed by improvement in the area under the receiver-operating curve (AUC) before and after its addition to the multivariate model. Cohen’s kappa coefficient was used to test the interobserver variability of CMR wall motion pattern and LV lead position. Statistical significance was determined by p < 0.05 on two-tailed analysis.Statistical analysis was performed with SPSS version 20  and SAS version 9.3 . Dichotomous variables were expressed as numbers and percentages, while continuous variables were expressed as mean ± standard deviation. Fisher’s Exact test was used to compare categorical variables. Continuous variables were compared by the Student’s type I (homogeneous) wall motion pattern, while 20 (61 %) had a type II (U-shaped) wall motion pattern. Two of the patients had bifascicular block (6 %); both of these patients had type I rather than type II contraction patterns. Type II patterns were present in 85 % of patients with favorable ECGs and 45 % of patients with non-favorable ECGs. Of the 20 patients with a type II pattern, 15 (75 %) had an inferior line of block and 5 (25 %) had an anterior line of block. The latest contracting segment was adjacent to the line of block in 19 of the 20 patients (95 %).Thirty-three patients were included in our analysis. Thirteen patients (39 %) were determined to have a type II patterns were more likely to have a favorable ECG, less significant scar on LGE, septal flash, and longer maximum opposing wall delays compared to those with type I patterns.Among the 33 patients in the cohort, the LV lead was concordant in 18 patients (54 %) and remote in 15 patients (46 %). True concordance, with the presence of the LV lead directly within the latest contracting segment, was observed in one patient; the remaining 17 (94 %) had the LV lead adjacent to the latest contracting segment. In 14 of these patients 82 %), the lead was in the next latest contracting segment. A full set of baseline characteristics for all patients and then grouped by echocardiographic response is shown in Table  %, the ltype II pattern, a concordant LV lead, and T2CL, as shown in Table The median time from CRT implantation to follow-up echocardiogram was 198 days (interquartile range 184 to 227 days). The overall echocardiographic response rate was 55 %. Responders were more likely to have NICM, a type II pattern regardless of lead location and all patients with a concordant LV lead position regardless of wall motion pattern . In those with non-favorable ECGs, the presence of T2CL was associated with significantly greater likelihood of response compared to those without T2CL .The response rate for patients with favorable ECGs was 69 %, compared to 45 % for those with non-favorable ECGs (type I pattern and 2 with a type II pattern). The response rate in patients with significant scar was 25 %, compared to 64 % for those without scar (p = 0.10). Four patients had an LV lead located in a non-viable segment, with a 25 % response rate in this group. The low prevalence of significant LGE precluded statistical analysis of the effect of T2CL in patients with scar; however, in the subgroup without significant scar, the presence of T2CL was associated with significantly greater response compared to non-T2CL .Thirty patients (91 %) underwent LGE imaging  and 8 patients (24 %) had significant scar (6 with a p = 0.036), a type II pattern , concordant LV lead location , and T2CL  were the only significant predictors of response. Variables included in multivariate analysis are shown in Table independent predictor of response. The addition of T2CL to NICM and a favorable ECG resulted in an increase in AUC for response from 0.69 to 0.84 (p = 0.038). The presence of significant scar was not evaluated in these primary analyses due to the low prevalence of significant LGE as well as an incomplete data set for this parameter for the three patients who did not undergo LGE imaging. Intermediary analyses with incremental addition of each covariate into the model along with T2CL are also shown; results did not deviate significantly between these intermediary models and the final model ; with an increase in AUC for response from 0.71 to 0.86.The exploratory addition of maximum opposing wall delay, presence of septal flash, and presence of significant scar to the multivariate model did not significantly change results, with T2CL remaining the only independent predictor of response  with a Cohen’s kappa coefficient of 0.75 (p < 0.0001). Two independent observers (GH and ML) reviewed 15 randomly selected biplane fluoroscopic images to assess if the LV lead was concordant or remote to the latest site, demonstrating excellent agreement (93 %) with a Cohen’s kappa coefficient of 0.87 (p = 0.001). In both cases, discrepancies were resolved by consensus review of the two observers to determine the final classification.Two independent observers (GH and JO) reviewed all 33 regional wall motion maps and categorized each as either type II left ventricular wall motion pattern and localization of a pacing lead concordant with the latest contracting LV site independently predicted echocardiographic response to CRT. It is likely that previously identified clinical predictors of response, such as NICM and a favorable ECG pattern are useful due to the relatively high proportion of type II patterns present in these groups. In addition to supporting this trend, our study showed that type II patterns are also present in other less favorable groups, for example, nearly half (45 %) of those with non-favorable ECG. To date, imaging of dyssynchrony has largely been regarded generically as a delay in mechanical contraction between the septal and lateral walls, and prospective utilization of these criteria for CRT selection has yielded disappointing results [We demonstrated that the combination of a  results . Recent  results , 11, 12.type I and type II [type I pattern is characterized by short trans-septal delay and homogenous slow LV activation towards the lateral wall, likely related to electromechanical uncoupling from myopathy instead of specific conduction system disease (i.e. of the left bundle branch). The type II pattern is characterized by prolonged trans-septal delay and an inferoseptal or anteroseptal breakout site with a corresponding functional line of block resulting in a “u” or “n” shaped LV activation pattern indicative of a primary electrical abnormality. “Correction” of the type II pattern with CRT is associated with mid-term clinical and echocardiographic improvement, while many patients with type I patterns fail to significantly respond [type II patients identified by invasive electrophysiologic mapping had overall improvement in echocardiographic dyssynchrony after CRT, while type I patients actually had worsening dyssynchrony [type II pattern likely represents a discrete line of conduction block more amenable to electrical resynchronization compared to the diffuse, homogenous conduction delay of type I.Dichotomous dyssynchrony patterns were first identified on invasive electrophysiologic mapping of endocardial electrical activation in patients with left intraventricular conduction delays and classified as  type II –24. The  respond , 15. Funynchrony . Thus, aThe discussion above linking mechanical contraction patterns and electrical conduction patterns depends on the amount of electro-mechanical (EM) coupling that is present. We previously conducted a study in patients undergoing CRT who had a pre-procedural CMR exam. During the CRT procedure, local intracardiac electrograms were taken at various sites, and electric times from the electrograms were correlated to mechanical contraction times from the CMR studies. We found that electrical and mechanical delay times were highly correlated in individual patients, indicating a high level of EM coupling .type I and type II patterns of wall motion in 52 patients planning to undergo CRT [type II pattern as the only independent predictor of echocardiographic response at 6 months. Similarly, we demonstrated a higher likelihood of response in type II patients alone , however, the likelihood of response was far superior in type II patients with a concordant LV lead (92 %). Although the type II pattern is more common in NICM, which is a dependable predictor of CRT response [type I pattern to be more common in patients with ischemic cardiomyopathy (ICM) and significant scar, however, only a small portion of our patients had ICM, precluding a subgroup analysis of the effects of T2CL within this group. In the study by Sohal et al., 48 % of the patients had ICM and type II patients with ICM had more than double the response rate of type I patients [type II pattern and response to CRT persisted after correcting for significant LV scar. Furthermore, another recent study has suggested that the presence of a septal flash is an important predictor of CRT response in addition to scar absence [Recently, Sohal et al. used CMR to define ergo CRT . Utiliziresponse , 26, botpatients . The rel absence . Our exptype II pattern) along with a particular site (the latest to contract) may yield the highest likelihood of response.Conventional CRT implantation methods targeting the most anatomically suitable lateral or posterior coronary vein may contribute to poor response. Often, the latest contracting LV segment is not located posteriorly or laterally . Furthertype II pattern was present in the majority (61 %) and may represent an opportunity to improve response by targeting this substrate.Currently, the ECG characteristics of true LBBB morphology with a QRS duration > 150 ms are considered the most important predictors of CRT response –6. Contetype II patients provides superior response; we simply demonstrated the independent association of these features with a higher likelihood of response. A prospective randomized interventional trial of CRT guided by CMR derived wall motion patterns in a larger group of patients would be the next step in the validation of this approach.This is a small study, which increases the likelihood of results occurring due to chance. An additional 1000 sample bootstrapping analysis was performed to ensure internal validity. Our method utilizes radial displacement of LV myocardium to characterize regional wall motion, which does not directly measure mechanical contraction onset or peaks. Although translational movement is corrected, passive motion cannot be totally excluded; however, our method has been validated against electrical activation patterns obtained by regional intra-operative sampling . The degtype II U-shaped LV wall motion pattern identified by CMR and concordant LV lead position predicts the highest likelihood of response among patients who meet current CRT implantation criteria. Improving CRT response rates may ultimately rely on patient selection by wall motion pattern and targeted LV lead placement, both of which are facilitated by CMR.The combination of a


Severe aortic stenosis (AS) induces diffuse interstitial myocardial fibrosis (MF). CMR late gadolinium enhancement (LGE) technique is useful to detect focal MF. The amount of MF is associated with worse long-term prognosis after aortic valve replacement surgery (AVR). Measurements of T1 relaxation times before and after gadolinium administration allow determination of myocardial extracellular volume fraction (ECV) in order to assess diffuse MF. In this study we investigated ECV and LGE prevalence and extent in severe AS, and compare them to left ventricular (LV), aortic valve (AV) function and MF by biopsy.We analyzed 11 patients with severe AS who underwent CMR before AVR. All patients had CMR examination on 1.5 T MRI system. Patients underwent cine-MR with SSFP sequence for ventricle function evaluation (measured by Simpson's method on the short-axis images) and LGE for MF detection (by thresholding technique), using CVi42 . T1 mapping used a modified Look-Locker sequence (MOLLI) before and 15-20 minutes after gadolinium administration. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and the hematocrit. In 4 cases, ECV was compared with MF measured on myocardial biopsy obtained at AVR, stained with Picrosirius red and expressed as collagen volume fraction (CVF). χ2, Fisher exact tests, t test and Mann-Whitney test when appropriate and for correlation Spearman test were performed using Stata 12.Baseline and MRI characteristics are shown on Table Our initial results have demonstrated that in severe aortic stenosis, ECV measurements of the remote area were similar between patients with and without LGE. Mean ECV measurements of the entire myocardium, including LGE areas, continued to be similar between patients without LGE and with moderate LGE extent. Comparison with myocardial biopsy has demonstrated a good correlation with extracellular volume by CMR.FAPESP grant 2013/06149-6.


Significant cardiovascular morbidity and mortality exists in COPD, independent of traditional risk factors, although the mechanisms are poorly understood. Lung hyperinflation, the presence of supra-normal residual volumes (RVol) at the end of expiration, is one postulated mechanism. We sought to investigate the impact of COPD on cardiac structure and function compared to a control group with equivalent cardiovascular risk and look at the relative contributions of lung hyperinflation, defined as RVol per cent predicted value >120 %, as well as traditional spirometric measures.45 consecutive COPD patients with lung hyperinflation randomised to the DEFLATA study underwent cardiac magnetic resonance at 1.5 T, spirometric and body plethysmographic assessment at baseline. 9 were excluded from this analysis due to a history of known cardiovascular disease and/or atrial fibrillation and the remaining 36 were compared to 44 consecutive patients with increased cardiovascular risk and normal spirometry who underwent CMR as part of the HAPPY London Study.There was no difference in age, gender, renal function or cardiovascular risk (QRisk) scores between the groups. Decreased Right ventricular (RV) and Left ventricular (LV) indexed end diastolic volumes (EDVI) were found in the COPD group  with decreased but preserved LV systolic function (LV Ejection fraction (EF) 60±7 vs 64±7 % p=0.005). RVEF was increased (63±7 vs 55±7 ml P<0.0001) as a consequence of preserved stroke volume . In the COPD group a 10% increase in RVol per cent predicted resulted in a 1.97 ml, 1.66 ml and 1.36 ml reduction in RVEDVI, LVEDVI and Left Atrial (LA) ESVI respectively  independent of age, sex, oxygen saturations, and Qrisk score. Furthermore a relationship between Rvol and LAEF  was found although not between LVEF or RVEF. Similar relationships were found for the expiratory flow limitation measure per cent-predicted Forced expiratory volume in 1 second (FEV1), although no relationship was found with regard to airflow obstruction .Morphological and functional differences exist between hyperinflated COPD patients and a control group with equivalent cardiac risk as defined by traditional risk factors. RVol and FEV1 per cent-predicted appear to be independently associated with cardiac chamber size. Effects are also seen on atrial function although right ventricular adaptation has ensured systolic function is preserved. Further studies are warranted to establish to what extent lung hyperinflation impacts on diastolic function and whether these changes are reversible.ISS has recieved a research grant from GSK. MYK is funded through Barts Charity.


Myotonic dystrophy type II ) is an autosomal dominantly inherited disease . Suffere42 .We prospectively enrolled 28 subjects  with a genetically confirmed diagnosis of PROMM. The criteria for exclusion were known cardiac diseases and contraindication for CMR. We assessed biplanar left-ventricular (LV) volumes, mass and function applying cine imaging  using a 1.5 T Scanner . Late enhancement imaging (LGE)  was performed to detect myocardial fibrosis about 10 minutes after injection of gadoteridol (0.2 mmol/kgbw). Furthermore, we used a previously described fat/water sequence[24 data sets were completed . All applied sequences were evaluable besides 3 fat/water images due to artifacts. None of the patients had wall motion abnormalities. Myocardial fibrosis were noticeable in 5 of the 24 subjects (2 women). No significant differences of age (p = 0.24) and LVEF (p = 0.09) were found between positive and negative LGE (Figure To the best of our knowledge this is the first systematic CMR study in patients with PROMM. Although all patients had preserved LVEF we could detect myocardial fibrosis in one fifth of all patients, suggesting CMR is feasible to detect such subclinical myocardial manifestations. Interestingly, we could also detect fat deposits. Further studies to look for diffuse alterations and correlations to clinical events should come next.University funding hold by Schulz-Menger, J.


A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance.CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed.The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation. Coronary heart disease (CHD) is a leading cause of death and disability worldwide. In a typical hospital setting, a variety of investigations may be used to diagnose CHD, risk-stratify, and determine the need for coronary revascularization. Myocardial perfusion scintigraphy by single-photon emission computed tomography (SPECT) is the most commonly used test worldwide for the assessment of myocardial ischemia, and there is a large body of evidence to support its prognostic value. Cardiovascular magnetic resonance (CMR) has high diagnostic accuracy for the detection of CHD, and the CE-MARC study demonstrated CMR's superiority over SPECT.Avoiding unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. Invasive coronary angiography has a risk of major complications of 1.7%. Furthermore, the dose and stochastic effects of x-ray radiation are frequently misjudged,A previous single-center trial (CECaT) indicated that invasive angiography could be avoided in 20% to 25% of patients using functional testing as an initial gatekeeper.a) National Institute for Health and Care Excellence (NICE) guidelines–based management (CG95),b) SPECT-guided management,The primary objectives are to determine if 3.0-T CMR-guided management is superior to (a) if in patients with a high PTL of CHD (61%-90%), noninvasive imaging (CMR or SPECT) is superior to NICE guidelines–based management, in terms of reducing the occurrence of unnecessary invasive angiography; (b) safety in terms of major adverse cardiovascular events (MACE) at 3 years between the CMR-guided care group and those receiving NICE guidelines–based management; (c) safety in terms of MACE at 3 years between the CMR-guided care group and those receiving SPECT-guided management; and (d) cost-effectiveness and impact on health-related quality-of-life (HRQoL) measures of a CMR-guided care strategy compared with NICE guidelines–based management and SPECT-guided management.Secondary objectives will determine  is a prospective, multicenter, multivendor, 3-arm parallel group, randomized controlled trial of patients referred to cardiology care for further evaluation of symptoms thought to be angina pectoris. A total of 1,200 patients with suspected CHD will be randomized on a 2:2:1 basis to receive CMR-guided care, SPECT-guided care, or NICE guidelines–based management  and 2.Statistical analysis will be performed by the Clinical Trials Research Unit, University of Leeds, and the Centre for Health Economics, University of York. The study population will be followed up prospectively for a minimum of 3 years to establish long-term MACE in each investigation arm. The study will be conducted in accordance with the Declaration of Helsinki and has been approved by the National Research Ethics Service.Subjects will be considered for inclusion if they are 30 years or older presenting to participating hospitals  with susThe treating clinician makes a clinical diagnosis of typical angina if the patient has all 3 salient features of angina  or atypical angina if they have 2 of 3.Patients will undergo risk stratification with their PTL of having CHD calculatedThe trial was funded by the British Heart Foundation (SP/12/1/29062). Additional support was received from the Leeds Teaching Hospital Charitable Foundation and the National Institute for Health Research, through the Local Clinical Research Networks.The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.1.Survey and reference scans prior to defining the short, vertical long, and horizontal long axes acquired with a balanced steady-state free precession (bSSFP), single-slice breath-hold sequence. bSSFP pulse sequence parameters dependent on scanner manufacturer and site. Typical parameters are as follows: echo time 1.3 milliseconds, repetition time 2.6 milliseconds, flip angle 40°, field of view 320-420 mm according to patient size, SENSE or GRAPPA acceleration, slice thickness 10 mm, and 30 phases per cardiac cycle.2.−1 min−1. Adequate hemodynamic response is assessed by either ≥10% heart rate increase or ≥10 mm Hg decrease in systolic blood pressure. If there is inadequate hemodynamic response, then the dose will be increased incrementally to 170 μg kg−1 min−1 and then 210 μg kg−1 min−1 for a further 2 minutes until hemodynamic response is achieved.Stress perfusion imaging performed with adenosine administered initially at 140 μg kgT1-weighted saturation recovery–prepared gradient echo-pulse sequence in 3 short-axis slices, planned using the 3/5 technique,kt-BLAST). First-pass contrast-enhanced study will be performed using a dual-bolus technique  for the main bolus preceded by the same volume of a 10% dilute contrast agent dose for the prebolus, both administered at a rate of 4.0 mL/s followed by a 20-mL saline flush.Perfusion image acquisition will use a 2-dimensional, 3.Resting wall motion and left ventricular function will be assessed with a contiguous stack of multiphase ventricular short-axis bSSFP cines .4.The rest myocardial perfusion study will use identical pulse sequence, slice positioning, and injection characteristics to the stress perfusion scan. If the stress perfusion scan was not of adequate quality , a repeat stress may be performed as alternative to the rest study.5.T1-weighted gradient echo-pulse sequence. Typical parameters are as follows: echo time 2.0 milliseconds, repetition time 3.7 milliseconds, flip angle 25°, acquired spatial resolution 0.70 × 0.70 × 10 mm3, and inversion time individually adjusted according to inversion time scout. LGE will be acquired with alternate heart beat acquisition  and long-axis and modified views acquired if clinically indicated.Late gadolinium enhancement (LGE) performed in 10 to 12 short-axis slices 10 to 15 minutes after step 4 with an inversion recovery–prepared Cardiovascular magnetic resonance will be performed on a clinical 3.0-T scanner using protocols that conform to international standards.99mTc-tetrofosmin or 99mTc-sestamibi . A weight-adjusted dose up to a maximum of 1000 MBq per examination will be used for stress and rest imaging, which will be performed within 5 days of each other.Radionuclide imaging will be performed according to local standard departmental practice conforming to both national and international guidelines.Stress examination will be performed with either treadmill or bicycle exercise, pharmacologic vasodilator stress (with adenosine or regadenoson), or a combination. Treadmill will involve exercise using the BRUCE or modified BRUCE protocol or bicycle ergometer typically commencing at 25 W increasing workload by 25 W every 2 minutes. Radioisotope tracer will be injected at peak stress.If pharmacologic stress with adenosine is used, the administration regimen will be comparable with the CMR protocol. If regadenoson is used, 0.4 mg will be delivered by rapid intravenous injection. Radioisotope tracer will be injected after at least 4 minutes of adequate hemodynamic/symptom response. Vasodilator stress may be combined with submaximal exercise.Images will be acquired on either a dual headed gamma camera or solid-state cadmium zinc telluride camera. Stress and rest images will be gated to the ECG, and attenuation correction will be used where routinely available.1.Scout scans.2.z-axis distance) will be used from tracheal bifurcation to the inferior border of the heart.Unenhanced scan with prospective gating and inspiratory breath-hold. A minimum scan length  and short-acting sublingual nitrates given. Computed tomography coronary angiography will be performed where possible, with a prospective gating technique using the minimum scan range planned from the unenhanced scan. Typical scan parameters are as follows: 0.625-mm collimation, pitch 0.2-0.4, 100-120 kV, and 400-830 mAs (adjusted according to body mass index). If retrospective gating is required, ECG dose modulation will be used to minimize radiation dose. The acquisition window will usually be centered at end-diastole (end-systole may be used at the discretion of the attending physician). In those with variable heart rates, time interval padding may be used to allow reconstruction of both the systolic and diastolic phase data sets. The exact scan parameters and radiation reduction algorithms used will be dependent on the hardware vendor. Iodinated contrast agent of 60 to 120 mL will be administered at a flow rate of 4.5 to 6.5 mL/s, followed by a bolus of normal saline  during an acquisition with inspiratory breath-hold. Either a test bolus or a bolus tracking technique may be used.−1 min−1 to achieve maximal hyperemia and hemodynamic steady state; pull-back assessment of diffuse disease or serial stenoses can be made. Adenosine will be administered as per CMR protocol. Totally occluded coronary arteries will have a default FFR value of 0.50 recorded; for lesions >90%, FFR will also be considered positive (0.50), and for lesions <40%, FFR will be considered normal (0.90).Angiography will be performed using a standard technique . Fractional flow reserve (FFR)  will be performed in all vessels ≥2.5 mm with stenosis ≥40% and ≤90%, following intracoronary nitrates, using adenosine at 140 to 210 μg kgAll test results will be reported by independent cardiology/radiology consultants with a minimum 5-year experience in the imaging modality. In accordance with usual clinical practice, all clinical data from all noninvasive imaging modalities will be available for the reporting physician to make an overall clinical judgement.Cardiovascular magnetic resonance analysis will be both visual and quantitative following international recommendations.Detection of hypoperfusion (ischemia), by visual comparison of stress, rest, and LGE scans, will be scored as 0 = normal, 1 = equivocal, 2 = nontransmural ischemia <50%, 3 = nontransmural ischemia ≥50%, or 4 = transmural ischemia in 16 segments of the 17-segment American Heart Association/American College of Cardiology model .Any infarct (scar) will be reported based on the LGE images (17-segment model), with scores of 0 = no hyperenhancement, 1 = 1%-25% mural thickness, 2 = 26%-50%, 3 = 51%-75%, or 4 = >75% allocated to each segment.A positive result  will by protocol necessitate referral for invasive angiography ± FFRSingle-photon emission computed tomography analysis will be both visual and quantitative. Local on-site reporting will include any regional wall motion abnormality . Each segment scored as 0 = normal, 1 = mild hypokinesia, 2 = severe hypokinesia, 3 = akinesia, or 4 = dyskinesia.Evidence of ischemia, by visual comparison of rest and stress scans, will be scored as 0 = normal, 1 = mild 51%-70%, 2 = moderate 31%-50%, 3 = severe 10%-30%, or 4 = absent <10% in each segment. Quantitative analysis will include summed rest score and summed stress scores, quantitative perfusion SPECT (QPS) defect extent (%), quantitative perfusion SPECT total perfusion deficit (%), end-systolic volume (mL), end-diastolic volume (mL), stroke volume (mL), and ejection fraction (%).The presence of artifacts including subdiaphragmatic activity affecting the inferior wall, significant patient movement, anterior attenuation, inferior attenuation, and left bundle-brunch block artifact will be recorded.A positive result (summed stress score ≥ 4), unless believed by the reporting clinician to represent attenuation artifact, will by protocol necessitate referral for invasive angiography ± FFR.The total Agatson CAC score from the unenhanced scan will be determined. If the CAC score is >0 and <400, a contrast-enhanced scan will be performed.Coronary stenosis will be graded as 0 = normal, 1 = minimal <25% stenosis, 2 = mild 25%-49%, 3 = moderate 50%-69%, 4 = severe 70%-99%, or 5 = occluded 100%. A positive result  will by protocol necessitate invasive angiography ± FFR.Invasive x-ray angiography will be interpreted visually by the performing clinician recording the coronary artery dominance, location, and visual degree (%) of all coronary stenoses in all major epicardial coronary arteries . FFR measurement will be recorded in all arteries ≥2.5 mm with a visually recorded diameter stenosis ≥40% and ≤90%. Where FFR cannot be performed due to clinical/safety reasons, quantitative coronary angiography (QCA) will be performed using validated commercial vendor software. In this instance, QCA measurements will be made during offline analysis by a single independent blinded observer at the Glasgow Angiographic core laboratory. Lesions will be considered significant if a coronary artery segment  analyzed by QCA has a percentage diameter stenosis of ≥70% in one view or ≥50% in 2 orthogonal views.On occasion where the attending cardiologist overrules the protocol requirement to proceed to invasive coronary angiography, this will be recorded as a protocol violation.Annual follow-up over the subsequent 3 years will be undertaken to record death (including cause), other MACE, and withdrawal. For alive patients, medical history since randomization, including details and dates of acute coronary syndrome (ACS), emergency or elective revascularization procedure, any admission for cardiovascular cause will be obtained and verified from hospital or family practitioner records. Details of any recent cardiovascular investigations will be taken. In addition, Office for National Statistics monitoring will be sought for deceased patients to determine the certified causes of death.The primary end point is unnecessary invasive coronary angiography occurring within 12 months in each arm. This will be defined at the time of coronary angiography by an FFR measurement of >0.80 in all vessels ≥2.5 mm in a patient-based analysis .•A negative FFR and positive noninvasive test result •A negative FFR in a high PTL (61%-90%) patient that proceeds directly to invasive angiography in the NICE guidelines–based strategy arm •A negative FFR and a negative noninvasive test result •A negative FFR and an inconclusive noninvasive test result in which angiography had to be performed to make the diagnosis An “unnecessary angiogram” will be defined as one of the following:For all patients, MACE at 12 months and a minimum of 3 years will be reported. Major adverse cardiovascular events will be defined as death due to cardiovascular cause, myocardial infarction .2 testSample size calculations were performed using nQuery 7.0, Statistical Solutions Ltd., Cork, Ireland. For the primary end point analyses, a sample size of 1,200  will provide 99% power to detect a difference of unnecessary angiography rates between CMR and NICE guidelines–based management—accounting for the 2:1 allocation ratio—and 94% power between CMR and SPECT-guided care  when controlling for the minimization factors. The estimated odds ratios, 95% CI, and The proportions of patients in the 3 groups with a MACE at 12 and 36 months and absolute differences in these MACE rates will be presented. This analysis will be performed both on the intention-to-treat and per-protocol basis. Periprocedural MI—type 4a (related to percutaneous coronary intervention [PCI]) and type 5 (related to coronary artery bypass grafting)—and planned revascularization (PCI or coronary artery bypass grafting) based on the index FFR results will be censored.The scores will be presented for the groups at 6, 12, 24, and 36 months. The scores for the dimensions of the Seattle Angina Questionnaire and Medical Outcomes Survey-Short Form 12 will be summarized by randomized group at each time point. Multilevel repeated-measures modeling will be used to estimate differences between the groups at all postbaseline time points . Residuals and predicted values produced from the multivariate models will be examined to assess the assumptions of the statistical model.Data will be monitored for completeness and quality by the Clinical Trials Research Unit. A full monitoring schedule including serious adverse events and adverse reactions will be established and agreed by the Trial Steering Committee and Trial Management Group. Ethical and safety considerations will be monitored by the DMEC . A qualiThe CE-MARC 2 trial is a prospective, multicenter, 3-arm parallel group, randomized controlled trial; it will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intention of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, HRQoL, and the cost-effectiveness of CHD investigation.S.P. is funded by a British Heart Foundation fellowship (FS/10/62/28409). C.B. has had educational and research grants and acted as a consultant for St Jude Medical Corporation with institutional reimbursement to the University of Glasgow. G.P.M. is funded by a National Institute of Health Research fellowship.


Visceral adipose tissue, a biologically active fat depot, has been proposed as a reliable marker for visceral adiposity and metabolic abnormalities. Effects of such adiposity on LV diastolic function and dyssynchrony remained largely unknown.We assessed pericardial fat (PCF) and thoracic peri-aortic fat (TPAF) by three-dimensional (3D) volume-vender multi-detector computed tomography (MDCT) . Echo-derived diastolic parameters and tissue Doppler imaging (TDI) defined mitral annular systolic (S’), early diastolic (E’) velocities as well as LV filling (E/E’) were all obtained. Intra-ventricular systolic (Sys-D) and diastolic (Dias-D) dyssynchrony were assessed by TDI method.p < 0.05). These associations remained relatively unchanged in multi-variate models. PCF and TPAF set at 81.68 & 8.11 ml yielded the largest sensitivity and specificity  in predicting abnormally high LV diastolic dyssynchrony, which was defined as Dias-D≧55 ms.A total of 318 asymptomatic subjects  were eligible in this study. Greater PCF and TPAF were both associated with unfavorable diastolic indices and higher diastolic dyssynchrony  contains supplementary material, which is available to authorized users. Heart failure (HF) has emerged as a rapid growing epidemic in recent years . There hAccumulating epidemiologic data have recently suggested that metabolic abnormalities accompanied by obesity, excessive body fat and systemic inflammation can confer higher heart failure risks –9, partiPericardial fat (PCF), which can be accurately quantified by various imaging tools and serve as a reliable marker of visceral adiposity , 15, hasFrom 2009 to 2013, we consecutively studied subjects who attended primary cardiovascular health survey in a tertiary medical center in Taipei, Taiwan. Participants with decompensated heart failure, unstable coronary events, symptomatic angina or those who underwent hemodialysis were precluded from this primary screen program. Detailed physical examination was performed as well as a thorough review of baseline characteristics, medical history including current smoking behavior and regular physical activity from structured questionnaires. Subjects with known cardiovascular disease history defined as previous myocardial infarction, coronary arterial disease, stroke, prior hospitalization for congestive heart failure and peripheral arterial disease were excluded. Subjects with history of atrial fibrillation, left bundle branch block or pacemaker implantation were also excluded. A total of 318 subjects after exclusion during study period were finally enrolled.Hypertension was defined as systolic blood pressure higher than 140 mmHg, diastolic blood pressure higher than 90 mmHg or previously diagnosed hypertension under medication control. Diabetes was defined as fasting glucose level more than 126 mg/dL or previously diagnosed diabetes under medication control. Hyperlipidemia was defined as those with known history and/or who use lipid-lowering drugs, such as statins or fibrates, on a daily basis.This study has been approved by Mackay Memorial Hospital Institutional Review Board with adherence to research ethics (IRB number: 14MMHIS161). All participants were adults and provided written informed consent to be included in the study.Hitachi 7170 Automatic Analyzer  was used to measure fasting and postprandial glucose levels (hexokinase method), HbA1c, creatinine (kinetic colorimetric assay), total cholesterol and triglyceride (TG). Lipid profiles including low-density lipoprotein (LDL) and high-density lipoprotein cholesterol (HDL) were obtained by homogenous enzymatic colorimetric assay. High-sensitivity CRP (hs-CRP) levels were determined by using a highly sensitive, latex particle-enhanced immunoassay Elecsys 2010 .Each subject underwent two-dimensional and color Doppler transthoracic echocardiogram  equipped with 2–4 MHz transducer at left decubitus position. Standardized echocardiography imaging protocol including measurement of left atrial dimension (LAD), wall thickness, LV volumes (biplane Simpson method), and LV mass (American Society of Echocardiography criteria)  were allFor pulsed wave TDI-based measures, highest temporal resolution with frame rates >100 frames/sec with caution to optimize the parallel alignment for TDI tracing with myocardial longitudinal motion was achieved for raw imaging recording for subsequent dyssynchrony analysis. Intra-ventricular horizontal dyssynchrony was presented as the absolute time-to-peak velocity difference of S’ and E’  between LV basal lateral and septal segments from apical 4-chamber views  study was performed by a 16-slice scanner  with 16 mm × 0.75 mm collimation, rotation time 420 ms and tube voltage of 120 kV. In one breath-hold, images were acquired from above the level of tracheal bifurcation to below the base of heart using prospectively ECG triggering with the centre of the acquisition at 70 % of the R-R interval. From the raw data, the images were reconstructed with standard kernel in 3 mm thick axial, non-overlapping slices and 25 cm field of view. Pericardial fat (PCF) and thoracic peri-aortic fat (TPAF) were quantified using a dedicated workstation . The semi-automated segmentation technique was developed for quantification of fat volumes. We traced the region of interest manually and defined fat tissue as pixels within a window of −195 to −45 HU and a window centre of −120 HU. PCF was defined as any adipose tissue located within the pericardium from the level of left main coronary artery to the cardiac base  were used to determine the independent association between adipose tissue volumes (both PCF & TPAF), LV structural/functional parameters and degree of dyssynchrony (Sys-D/Dias-D). The area under the receiver-operator characteristic curve (AUROC) for PCF/TPAF in identifying significant LV septal and lateral wall (systolic and diastolic) timing differences was used as a summary measure of clinical outcome measure for dyssynchrony , with corresponding 95 % confidence interval (CI) was further reported.All data were analyzed using a commercial software STATA 8.2 package . The significance of p level  for all analysis was two-sided, with a value less than 0.05 considered statistically significant.p < 0.05). There were also significant differences in age and diastolic blood pressure across PCF tertile groups (both p < 0.05).Of all 318 subjects  enrolled, 102 (32.1 %) had hypertension, 46 (14.5 %) had diabetes, and 109 (34.3 %) had hyperlipidemia with a mean PCF and TPAF volume of 80.6 ± 33 & 7.89 ± 4.47 ml, respectively. Median PCF volume was 75.98 ml (interquartile range = 39.02), and median TPAF volume was 7.02 ml (interquartile range = 5.08). The association between baseline demographics, biochemical data and visceral adiposity are summarized in the first half of Table p < 0.05). PCF was also associated with elevated E/E’ ratio, prolonged IVRT and increased interventricular septum thickness . TPAF was associated with significant increases in LV end-systolic volume and both wall thickness . There was no significant difference in LV ejection fraction (LVEF) with either adipose tissue. In Table p < 0.05). Increased BNP was also borderlinely associated with diastolic dysfunction (p = 0.06).There were 148 subjects with Grade 1 diastolic dysfunction and 70 subjects with Grade 2 diastolic dysfunction. The association between echocardiographic data and visceral adiposity was summarized in the latter half of Table p < 0.001). In Fig. p < 0.001). PCF and TPAF set at 67.31 & 6.69 ml yielded the largest sensitivity and specificity  in predicting diastolic dysfunction. It should be noted here that the p values yielded by ANOVA .In Table p < 0.01). In Fig. p < 0.001). In the uni- and multi-variate regression models of Table p < 0.001).There were 28 subjects with abnormally high diastolic dyssynchrony (Dias-D≧55 ms) and 22 subjects with systolic dyssynchrony (Sys-D≧60 ms). As seen in Table p < 0.001), when defined by the aforementioned criteria (Dias-D≧55 ms). PCF and TPAF set at 81.68 & 8.11 ml yielded the largest sensitivity and specificity  in predicting abnormally high LV diastolic dyssynchrony , which is contrary to most worldwide epidemiologic studies. One possible explanation of our unusual findings might be that our average BMI is relatively normal (only 28 subjects had BMI > 30). On the other hand, the strong correlation that we demonstrated with advanced tissue Doppler metrics suggested a specific process linking pericardial fat to subclinical diastolic dysfunction that might be initiated much earlier than systemic metabolic derangements or excessive body mass accumulation. The specific effects of pericardial fat on cardiac structure and function via various mechanisms have been proposed in previous literature [Our team has reported previously that pericardial fat was independently associated with metabolic derangements, fatty liver disease and systemic inflammation . Althougterature . Compresterature . Pericarterature , 25.Besides LA enlargement, we also observed a slight but significant increase in LV wall thickness among subjects with larger PCF or TPAF. Although diastolic dysfunction or dyssynchrony is not uncommon in people with normal wall thickness, LV hypertrophy and hypertensive heart disease are indeed the most important causes of HFpEF , 27. TheRecently, it has been discovered that dyssynchrony is not as uncommon as previously assumed, and can occur to some extent even in the normal heart . Due to As previously mentioned, both systolic and diastolic dyssynchrony have been found to exist in HFpEF, though diastolic dyssynchrony does seem to be more prevalent and may occur exclusively , 4. ThisOne recent study using strain imaging showed that obesity is a significant independent predictor of intra-ventricular dyssynchrony . AnotherDue to its proximity to the myocardium and the same coronary blood supply, pericardial fat may have stronger correlations with coronary vasculopathy , cardiacThere are several limitations in our study. The first, our study has a male gender predominance, which may be somewhat biased. Secondly, this survey is retrospective and cross-sectional, without longitudinal follow up or validation with clinical outcomes. Thirdly, our data come from asymptomatic Asian participants who underwent primary cardiovascular health survey, and who therefore may not be fully representative of the broader general population in daily out-patient clinics. Finally, only basal septal and lateral segments were used to calculate dyssynchrony, which may be an overly simplistic estimate. We also acknowledge that our data regarding LA remodeling were mainly focused on LA diameter rather than 2-dimensional echo-based volume measurements.Our study provides valuable insights into the underlying of potential pathophysiologic mechanisms that visceral adipose tissue may exert several biological effects on myocardial contractile or diastolic functions and coordination, leading to impaired diastolic dysfunction, more elevated filling pressures and prolonged dyssynchrony, even in asymptomatic subjects. Our findings are critical in the conceptual framework of current understanding in obesity or metabolic derangements related myocardial asynergy and predisposition to preserved ejection fraction HF development. Excessive visceral adiposity burden linked to metabolic derangements, when assessed by CT, may thus serve as a possible marker or target for associated diagnostic purposes and future therapeutic intervention in these population.