The aim of the study was to compare the two approaches to chronic right ventricular pacing currently adopted in clinical practice: right ventricular apical (RVA) and non-RVA pacing. Chronic RVA pacing is associated with an increased risk of atrial fibrillation, morbidity, and even mortality. Non-RVA pacing may yield more physiologic ventricular activation and provide potential long-term benefits and has recently been adopted as standard procedure at many implanting centers. The Right Pace study was a multicenter, prospective, single-blind, nonrandomized trial involving 437 patients indicated for dual-chamber pacemaker implantation with a high percentage of RV pacing.p = 0.609), as were the rates of the composite of death due to any cause, hospitalization for heart failure, or an increase in left ventricular end-systolic volume ≥ 15% as compared with the baseline evaluation . After central adjudication of X-rays, comparison between adjudicated RVA (239 patients) and non-RVA (170 patients) confirmed the absence of difference in the rates of primary (p = 0.402) and secondary (p = 0.941) outcome. RV lead-tip target location was the apex or the interventricular septum. RVA (274) and non-RVA patients (163) did not differ in baseline characteristics. During a median follow-up of 19 months , 17 patients died. The rates of the primary outcome of death due to any cause or hospitalization for heart failure were comparable between the groups . In patients with indications for dual-chamber pacemaker who require a high percentage of ventricular stimulation, RVA or non-RVA pacing resulted in comparable outcomes. This study is registered with ClinicalTrials.gov (identifier:  Chronic right ventricular apical (RVA) pacing is associated with an increased risk of atrial fibrillation, morbidity, and even mortality . SeveralPacing at nonapical right ventricular (non-RVA) sites may yield more physiologic ventricular activation and less dyssynchrony and provide potential long-term benefits , 5. DespThe aim of the Right Pace study was to compare the two approaches to chronic pacing of the right ventricle currently adopted in clinical practice: RVA and non-RVA pacing. In the present analysis, we compared the long-term outcome of right ventricular pacing according to the intended and actual lead position.The Right Pace study was a multicenter, prospective, single-blind, nonrandomized trial. A detailed description of the rationale and methods of the study has been published elsewhere . PatientPatients meeting eligibility requirements underwent baseline evaluation, which included demographics and medical history, clinical examination, and 12-lead electrocardiogram. They then underwent implantation of a dual-chamber pacemaker with standard right atrial and right ventricular leads. The target location for the right ventricular lead tip was the apex or the interventricular septum, according to the clinical practice of the center. Indeed, investigators were divided on the basis of their prior experience of nonapical pacing-lead implantation and the clinical practice adopted in their centers. X-rays in the anteroposterior, right oblique, and left oblique projections (>30°) were taken and stored. An echocardiographic evaluation was performed to assess the left ventricular dyssynchrony induced by right ventricular pacing. Dyssynchrony was detected by means of tissue Doppler imaging and measured as the delay between the septal and lateral peak systolic velocity curves (SLD). An SLD of 41 ms or more was defined as a significant left ventricular mechanical delay . After dThe primary endpoint was the composite of death due to any cause or hospitalization for heart failure. The secondary endpoint was the composite of death due to any cause, hospitalization for heart failure, or an increase in left ventricular end-systolic volume of 15% or more as compared with the baseline evaluation. Additional endpoints were the first episode of atrial fibrillation documented during the follow-up period and the ventricular pacing parameters.X-rays and electrocardiograms were reviewed in independent core laboratories not directly involved in the implanting procedures. Lead position was adjudicated according to published criteria .t-test for Gaussian variables. The Mann-Whitney U test and the Wilcoxon nonparametric test were used to compare non-Gaussian variables for independent and paired samples, respectively. Differences in proportions were compared by applying chi-square analysis or Fisher's exact test, as appropriate. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed by means of a Cox regression model, in which baseline predictors were considered as fixed covariates and the primary endpoints were considered as time-dependent covariates. We included in the multivariate Cox model any variable with p < 0.05 on univariate analysis. A p value < 0.05 was considered significant for all tests. All statistical analyses were performed by means of STATISTICA software, version 7.1 .All endpoints were initially analyzed as intention-to-treat, according to the lead site assigned at the implanting center. A predefined on-treatment analysis was also performed according to the final lead position, as determined by the lead adjudication committee. Descriptive statistics are reported as means ± SD for normally distributed continuous variables, or medians with 25th to 75th percentiles in the case of skewed distribution. Differences between mean data were compared by means of a From June 2012 through September 2014, 437 patients referred to the study centers for pacemaker implantation met eligibility requirements and underwent baseline evaluation. Of these, 274 were referred to centers routinely performing standard apical positioning of the right ventricular lead, while in 163 patients the target location for the right ventricular lead tip was the interventricular septum, in accordance with the clinical practice adopted in the remaining centers. Demographic data and clinical parameters were similar between the study groups at the time of enrollment , except X-rays were available for core laboratory adjudication of the lead position in 409 patients. Apical positioning of the right ventricular lead was not confirmed in 56 (20%) patients in the RVA group. Similarly, in 21 (16%) patients in the non-RVA group, the adjudicated pacing site was the apex. Therefore, the adjudicated RVA group numbered 239 patients and the adjudicated non-RVA group, 170 patients.p = 0.609), as were the rates of the composite of death due to any cause, hospitalization for heart failure, or an increase in left ventricular end-systolic volume of 15% or more as compared with the baseline evaluation . Comparison between the adjudicated RVA and adjudicated non-RVA groups confirmed the absence of difference in the rates of the primary  and secondary outcome . The pacing site, according to local or core laboratory assignment, did not show any association with outcomes on multivariate analysis (p = 0.002). Moreover, the risk of atrial fibrillation was comparable between groups. p = 0.244).Patients were followed up until December 2015. During a median follow-up of 19 months , 17 patients died (12 cardiac deaths and 5 noncardiac deaths). The rates of the primary outcome of death due to any cause or hospitalization for heart failure were comparable between groups . The pacing parameters were satisfactory in both groups at baseline and at the last observation, with pacing thresholds consistently below 1 V . NonetheThe present study showed that, in patients with indications for a dual-chamber pacemaker and requiring a high percentage of ventricular stimulation, pacing of the right ventricle at apical or nonapical right ventricular sites resulted in comparable clinical outcomes over 2 years.The incidence of death, hospitalization for heart failure, or progression of heart failure, as measured by a significant increase in left ventricular end-systolic volume, was similar with standard RVA or alternative non-RVA positioning of the lead, in accordance with the clinical practice adopted in the centers.Since the advent of intravenous leads, the apex has become the standard site for right ventricular lead implantation, as it ensures simple placement and greater lead stability and reliability. However, in subjects with normal left ventricular systolic function who require permanent pacing, RVA stimulation is associated with an increased risk of atrial fibrillation, morbidity, and even mortality . These oRight ventricular septal placement has been proposed as an alternative approach for the safe implantation and possible easy extraction of pacemaker and implantable defibrillator leads , 11. MorDespite the lack of strong evidence in favor of nonapical pacing and the difficulty of placing the lead and accurately classifying  the finaTherefore, the aim of the present study was to compare the effects of right ventricular pacing when the lead is positioned in the apex or at nonapical sites, according to the routine clinical practice of the participating centers. The investigators were divided on the basis of their prior experience of pacemaker implantation with apical or nonapical lead positioning, in order to reduce the bias related to the learning curve and to provide results applicable to routine clinical practice.We demonstrated that the incidence of death, hospitalization for heart failure, or progression of heart failure over 2 years were similar with apical or non-RVA positioning of the lead. Therefore, we confirmed, in clinical practice, the negative results yielded by non-RVA pacing in the setting of a controlled clinical study . We alsoThe present findings extend our preliminary analysis of the acute echocardiographic effects of right ventricular pacing . Indeed,In the present study, about 50% of patients met the endpoint of heart failure progression at 2-year follow-up examination. A comparable rate of events was reported in patients with atrioventricular block, New York Heart Association (NYHA) class I, II, or III heart failure, and a left ventricular ejection fraction of 50% or less, enrolled in the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) study . HoweverThe pacing site, according to local or core laboratory assignment did not show any association with outcomes on multivariate analysis. Only the baseline ejection fraction turned out to be an independent determinant of incipient heart failure. This suggests that patients requiring a high percentage of ventricular stimulation and with initial systolic dysfunction are at higher risk of further deterioration; non-RVA pacing seemed unable to prevent this worsening. Therefore, other pacing strategies should be investigated as alternative approaches to preventing the drawbacks of RVA stimulation.Our results confirm previous findings , 18, in The currently adopted approaches to ventricular pacing, RVA and non-RVA, seemed equally feasible. Indeed, we reported few lead-related adverse events, and the pacing parameters were satisfactory in both study groups at the baseline and at the last observation.The main limitation of the present study is the lack of randomization. However, the study was designed in order to obtain an unbiased representation of current clinical practice and to compare two approaches currently adopted as standard procedures at many implanting centers. Moreover, owing to the nonrandomized nature of the study, the groups were very different in size.In patients with indications for a dual-chamber pacemaker who require a high percentage of ventricular stimulation, the two approaches currently adopted in clinical practice, that is, RVA and non-RVA pacing, resulted in comparable outcome and appeared equally safe.


Myocardial fibrosis (MF) is a deleterious consequence of aortic valve stenosis (AVS). Global longitudinal strain (GLS) is a novel left ventricular (LV) functional parameter potentially useful to non-invasively estimate MF. MicroRNAs (miRNAs) are non-coding small ribonucleic acids (RNA) modulating genes function, mainly through RNA degradation. miRNA-21 is a biomarker associated with MF in pressure overload. The aim of the present study was to find an integrated algorithm for detection of MF using a combined approach with both bio- and functional markers.2. To evaluate tissue miRNA components, sections 2-μm thick were cut using a microtome blade for each slide. Regression analysis was performed to test association between dependent variable and various predictors included in the model.Thirty-six patients  with severe AVS and preserved LV ejection fraction (EF), candidate to surgical aortic valve replacement (sAVR) were enrolled. Clinical, bio-humoral evaluation  and a complete echocardiographic study, including GLS and septal strain, were performed before sAVR. Twenty-eight of those patients underwent sAVR and, in 23 of them, an inter-ventricular septum biopsy was performed. Tissues were fixed in formalin and embedded in paraffin. Sections were stained with Hematoxylin and Eosin for histological evaluation and with histochemical Masson trichrome for collagen fibers. The different components were calculated and expressed as micrometers2 = 0.30; p = 0.02; SSL: R2 = 0.36; p = 0.01; SL-Sr: R2 = 0.39; p < 0.001; SL-SrE: R2 = 0.35; p = 0.001). miRNA-21 was mainly expressed in fibrous tissue (p < 0.0001). A significant association between MF and plasmatic miRNA-21, alone and weighted for measures of structural  and functional  remodeling, was found.Despite a preserved EF (66 ± 11 %), patients presented altered myocardial deformation parameters . The extent of MF showed an inverse association with both GLS and septal longitudinal deformation indices (GLS: RIn AVS, MF is associated with alterations of regional and global strain. Plasmatic miRNA-21 is directly related to MF and associated with LV structural and functional impairment. Aortic valve stenosis (AVS) is the most common valvular heart disease in Western Countries , 2. In pAccordingly, robust and repeatable measures of MF that may be applied in the clinical field are eagerly awaited.Nevertheless, the evaluation of patients with AVS is generally limited to the assessment of flow-dependent parameters  that reflect only the “valvular side” of the pathology, disregarding LV components of disease –5.Beside the endo-myocardial biopsy (gold standard), not ethically feasible in a clinical setting, a series of biomarkers and cardiac imaging techniques have been lately proposed to combine tissue parameters with functional evaluation. In this respect, the evaluation of LV deformation by Speckle Tracking Echocardiography (2D-STE) has been shown to allow a better assessment of cardiac contractile function than traditional parameters [i.e. Ejection Fraction (EF)], giving the chance to assess the presence of subtle alterations of LV systolic performance. In particular, regional and global longitudinal strain (GLS), showed a better and earlier diagnostic power over EF, becoming reference indicators for the precocious assessment of sub-clinical LV functional impairment –12. MoreMicroRNAs (miRNAs) are non-coding small ribonucleic acids (RNAs) that modulate the expression of target genes inducing mRNA degradation. The expression of miRNAs is associated with multiple pathological processes that affect also the cardiovascular system , 16.A regulatory role for miRNA-21 has been evidenced in LV myocardial remodeling induced by hemodynamic stress , 18.Recent reports indicate that the presence of circulating miRNAs may reflect specific cardiovascular pathologies and could be a useful biomarker for different cardiovascular diseases.Accordingly, the evaluation of both miRNA (as a biomarker) and GLS , might allow an integrated assessment of the pathophysiological relationship between MF and adverse LV remodeling.the presence of MF  both with gold standard histologic method and with an advanced laser micro-dissection methodology (tissue miRNA-21), in patients with severe AVS;the presence of a direct association between plasmatic and tissue pool of miRNA-21;the relationship between 2D-STE parameters, MF  and plasmatic/tissue miRNA-21 expression levels, in order to develop a non-invasive detection of myocardial fibrotic burden.With these considerations in mind, we aimed at assessing:2; AVAi < 0.6 cm2/m2) and preserved EF, were prospectively evaluated in University of Pisa Hospital (A.O.U.P) for sAVR. Patients underwent laboratory analysis , and trans-thoracic echocardiography . Twenty-eight patients were finally submitted to sAVR , 23 of whom (in 5 patients under-sampling/biopsy not performed) underwent intra-operatory basal inter-ventricular septum biopsy to evaluate MF (23 patients) and tissutal levels of expression of miRNA-21 (20 patients). All patients signed an informed consent, approved by local ethical committee, conform to the ethical guidelines of the 1975 Declaration of Helsinki. We excluded patients with at least one of the following: age < 18 y.o., significant major comorbidities , inability to sign consent, pregnancy, poor acoustic window, ischemic heart disease , associated valvular disease of moderate-severe degree, non-degenerative AVS, diskynetic septum .Thirty-six consecutive patients with severe symptomatic AVS . Patients were imaged in the left lateral decubitus position and data were acquired with a 4 MHz (M4S) transducer at a depth of 16 cm in the parasternal (long- and short-axis views) and apical views . All parameters were derived according to current indications, and considered in relation to their established reference ranges , 20.i). The LV end-diastolic and end-systolic volumes were measured from the apical two- and four-chamber views, and EF was calculated using the Simpson’s rule. LV diastolic function was evaluated using early (E wave) and late (A wave) trans-mitral velocities, the E/A ratio, and the E wave deceleration time obtained from the spectral pulsed-wave Doppler recordings. In addition, TDI was performed, adjusting gain and frame rate to get an appropriate tissue characterization. The aortic valve area  was calculated by the continuity equation, and the maximum pressure gradient across the restrictive orifice was estimated by the modified Bernoulli equation. Mean trans-aortic pressure gradient was calculated averaging the instantaneous gradients over the ejection period on the continuous-wave Doppler recordings. As a measurement of global left ventricular afterload, the valvulo-arterial impedance (ZVA) was calculated. Finally, color Doppler echocardiography was performed after optimizing gain and Nyquist limit in order to evaluate the presence of regurgitant valve disease. The severity of valvular regurgitation was determined on a qualitative scale , according to the current guidelines [LV dimensions were calculated from the standard M-mode/2D images at the parasternal long-axis views and included LV diameters and end-diastolic thickness of the interventricular septum and posterior wall. Left ventricular mass was calculated and corrected by the body surface area to derive mass index . We limited the analysis to the global longitudinal component of strain . Quantifications were performed using the available software , as described previously –23. For In 22 patients, in addition to coronary angiography, standard left heart catheterization was performed before sAVR. Peak-to-peak gradient, invasive end-diastolic pressure  and semi-quantitative aortic regurgitation were evaluated.the overall myocardial area occupied by the myocytes and connective tissue (fibrotic area);myocyte areaconnective areaconnective/overall myocardial area (ratio % as MF grading)In 23 patients undergoing sAVR, concomitant intra-operatory basal left-side inter-ventricular septum biopsy was performed to assess MF, as previously described –26. BrieAll measurements were made by two expert pathologists without knowledge of the clinical data .4-micron sections were dewaxed in xylene and rehydrated through graded alcohols to water. Antigen retrieval was performed microwaving sections for 9 min in citrate/EDTA buffer (pH 7.8). Not specific peroxidase activity was blocked with 3 % hydrogen peroxidase for 15 min, and non-specific binding prevented by incubation with normal goat serum for 10 min. Afterwards, incubation with anti-vimentin mouse monoclonal antibody  and anti-CD45/LCA rabbit monoclonal antibody  was performed for 1 h at room temperature. A biotin conjugated goat derived secondary antibody was applied followed by the Vectastain Elite ABC kit (Vector Laboratories). Slide were incubated with diaminobenzidine tetrahydrochloride (DAB) and counterstained with hematoxylin. Peripheral blood samples were collected using specific tubes (PAXgene Blood RNA Tube) included in the commercial systems for collection and immediate stabilization of peripheral blood RNA .For 20 biopsy specimens laser microdissection (LSMD) was performed. Sections 2-μm thick were cut from each case using a new microtome blade for each slide. The PALM MicroBeam laser micro-dissector from Carl Zeiss was used to select and collect cardiomyocytes and fibrotic cells to be studied separately.Blood RNA was purified using the commercial kit PAXgene Blood RNA Kit . The quantity of extracted RNA was estimated with Qubit 2.0 Fluorometer (Life Technologies) by using 2ul of undiluted RNA solution. Yield ranged from 50 to 500 ng/ul of RNA. Microdissected samples were incubated at 55 °C overnight upside-down with 50 μl of lysis buffer and 10 μl of proteinase K. The day after the samples were loaded in Maxwell 16 Instrument (Promega) to extract RNA.MicroRNAs were reverse transcribed from 6 µl of total extracted RNA sample using the miScript II RT Kit (QIAGEN). cDNA from micro dissected samples was pre-amplified prior to real-time PCR analysis of miRNA. miRNA expression analysis were performed in triplicate using 1 µl of diluted cDNA as a template for real-time PCR with the miScript SYBR Green PCR Kit (QIAGEN) and the miScript Primer Assays ) according to manufacturer’s instructions on the CFX96 Real Time system c1000 thermal cycler (BIORAD).Data analysis was performed using the Bio-Rad CFX Manager Software v3.1 and Microsoft Excel. miRNA 21 expression was calculated using SNORD61 expression level as reference and the relative normalized expression ∆∆Cq formula.U test when non-Gaussian. Univariate linear regression analysis was performed to test association between dependent variable and various potential predictors included in the model. We assessed also the association between Myocardial Fibrosis (Y) and Plasmatic miRNA-21 (X) weighted for left ventricular mass indexed for BSA and septal longitudinal strain, respectively. The threshold for statistical significance was p < 0.05. In order to preserve the statistical meaning of regression analysis (direct/inverse correlation/association), in the text we considered global longitudinal strain/systolic strain rate in absolute value. Using a c-statistic approach we derived the miRNA-21 value with the best combination of sensitivity and specificity for discrimination of patients with a significant amount of MF (more than 10 % of the specimen).The data sets were assessed for normality with the Kolmogorov–Smirnov test. Continuous variables are described as mean ± standard deviation (SD). Otherwise as median (with minimum/maximum). Categorical data are reported as percentage. Plasmatic and tissue miRNA-21 levels of expression where measurable were treated as continuous variables. Continuous variables were compared using the Mann–Whitney The following statistic package was used: Medcalc 12.7 . The characteristics of the population regarding clinical, laboratory and echocardiographic parameters are shown in Tables VA). Even if conventional indices of global systolic function were preserved , more sensitive parameters of longitudinal function  was observed Table .2 = 0.20; p = 0.006) and a significant inverse relationship with BNP levels . Modest inverse relationships between LVMi and AVAi , ZVA  and GLS , were also observed. Septal sub-analysis showed higher impairment of deformation indices and a significant direct relationship of SSL with stroke volume .In particular, GLS showed a direct relationship with indexed LV stroke volume (SVi) (RA variable amount of MF (with absence of inflammatory cells) was a common finding in patients who performed biopsy.To distinguish fibroblasts from inflammatory cells, immunohistochemistry was performed on myocardial fibrosis for vimentin and CD45. Figure 2 = 0.31; p = 0.03) and showed an inverse relationship with SVi . Moreover, MF showed a significant inverse relationship with deformation indices   with EDPi . Moreover, MF showed no association with afterload parameters, including AVAi, Z2 = 0.32 and p = 0.01; GLS: R2 = 0.34 and p = 0.008). Plasmatic miRNA-21 concentrations (n = 30) demonstrated a significant direct relationship with whole MF  and interstitial miRNA-21 compartment .While miRNA-21 was expressed both in myocytes and interstitial tissue, it resulted significantly more expressed in fibrous tissue  and LV function parameters  for discriminating patients with significant MF .No gender-based differences were found in the study.Patients with severe AVS show abnormalities of regional and global left ventricular myocardial strain, reflecting both pressure overload and geometric remodeling. These deformation abnormalities are related with the level of invasively measured MF (gold standard);The expression of textural miRNA-21 determined with laser micro-dissection may document its pathophysiological role in AVS. In particular, we focused on interdependence between textural miRNA-21 and fibrogenic stimulus induced by an abnormal left ventricular pressure overload;Circulating miRNA-21 (biomarker) levels are high in patients with severe AVS, reflecting the presence of significant myocardial fibrosis (defined as MF % higher or lower than 10 %).The main findings of the present paper are:Conditions of LV pressure overload determine a deep remodeling of the extracellular matrix, with the secondary deposition of MF. In the clinical setting, MF is known to be a deleterious consequence of AVS, contributing to systo-diastolic alterations and arrythmogenicity, affecting patients’ prognosis and quality of life after AVR. Meanwhile, we should not forget that in AVS, the paradigm “Pressure overload—LV remodeling—Myocardial hypertrophy—interstitial and later replacement fibrosis” remains still not so definite: indeed, there is a wide variation, independent from the stage of the disease . Thus, some patients with severe AVS have normal ventricular structure and no/mild fibrosis (10–30 %) while patients with only moderate AVS may have extensive hypertrophy and large amount of fibrosis , 25–27.In our study population, despite a preserved EF, we found a significant amount of MF at endo-myocardial biopsy, confirming the insensitivity of EF in revealing subtle myocardial textural alterations. On the contrary, as previously reported, myocardial deformation parameters, assessed by 2D-STE, were altered (in a context of preserved EF) and inversely related to global afterload and remodeling parameters (LVMi) , 28, 29.In attempting to estimate MF, many non-invasive imaging modalities showed good correlation with tissue data , 31. To In our study, we did not find a significant association between MAPSE or TDI (systolic velocities) and textural parameters. These results are in line with recent studies conducted in patients with Hypertrophic Cardiomyopathy that underwent septal miectomy. In fact, deformation parameters showed a strict correlation with myocardial fibrosis, while there was no association between MF and conventional echo parameters, including TDI , 34. In Recent evidences showed a key role for miRNAs, including miRNA-21, in cardio-vascular pathophysiology. However, only few recent papers evaluated their involvement in human heart, considering plasmatic and (seldom) tissue pools . SeveralTo our knowledge, this is the first paper evaluating tissue miRNA expression in biopsies of patients (in vivo) with AVS with LSMD, a more precise method respective to in situ hybridation (FISH).In line with previous findings, tissue expression of miRNA was higher for interstitial compartment than myocardial tissue , with noRecently, miRNA plasmatic levels confirmed their strong fibrogenic implications in other similar contexts .This may also open, in perspective, to myocardial fibrosis inhibition targeting, as very recently shown by Gupta et al. in animal models of acute allograft cardiac transplantation. We propose a complementary role of echocardiographic speckle tracking and plasmatic miRNA-21 analysis: the identification of the remodeling process (at macroscopic and tissue level) combined with a refined functional approach. In particular, the evaluation of plasmatic miRNA together with GLS  could help in better stratifying those patients that currently fall in a diagnostic “gray zone” of AVS severity. Then, we can speculate a potential clinical implication in terms of clinical practice/safety  and cost reduction . Present results underscore the tight relationship between valve and myocardium , suggesting that only a combined evaluation of both variables may allow a complete evaluation of patients with AVS .The present work was designed as a pilot study. The main limitation of the study is its small sample size and, at present, the absence of a follow-up. Analysis of plasmatic miRNA-21 is promising, but must be validated in larger studies, as its prognostic role and remodeling implications. To define a significant amount of MF evaluated with myocardial biopsy, we arbitrarily decided the cut-off of 10 %, according to the literature , 24.So far, above all due to the limited cases collected, we didn’t have the objective to derive cut-off for plasmatic/tissue values of miRNA-21.Finally, this study was not designed to identify risk-factors associated with MF in patients with AVS. Therefore, it is possible that the small number of patients fails in showing significant differences between subjects with similar age and cardio-vascular risk profiles . Anyway, consistent with previous and larger observations –27, the In patients with severe AVS, myocardial fibrosis was associated with significant alterations of both plasmatic and textural miRNA-21 (biomarker) levels, as well as with impairment of regional and global longitudinal strain . This combined bio-humoral and functional evaluation could allow a better definition of the remodeling process that takes place in AVS, possibly further improving risk stratification of patients. Prospective studies in larger populations of patients with AVS, are needed to better analyze the effective prognostic value of this imaging and bio-humoral integrated approach, in order to shift the clinical focus also on myocardium, beside valvular apparatus.


Disease progression and heart failure development in Ebstein’s Anomaly (EA) of the tricuspid valve is characterized by both right and left ventricular (LV) deterioration. The mechanisms underlying LV dysfunction and their role in heart failure development are incompletely understood. We hypothesized that LV dyssynchrony and impaired torsion and recoil mechanics induced by paradoxical movement of the basal septum may play a role in heart failure development.31 EA patients and 31 matched controls underwent prospective cardiovascular magnetic resonance (CMR). CMR feature tracking (CMR-FT) was performed on apical, midventricular and basal short-axis and 4D–volume analysis was performed using three long-axis views and a short axis cine stack employing dedicated software. Circumferential uniformity ratio estimates (CURE) time-to-peak-based circumferential systolic dyssynchrony index (C-SDI), 4D volume analysis derived SDI (4D–SDI), torsion (Tor) and systolic (sysTR) and diastolic torsion rate (diasTR) were calculated for the LV. QRS duration, brain natriuretic peptide, NYHA and Total R/L-Volume Index (R/L Index) were obtained.p < 0.01) and showed more LV dyssynchrony . There were significant associations of LV dyssynchrony with heart failure parameters and QRS duration. Although torsion and recoil mechanics did not differ significantly (p > 0.05) there was an association of torsion and recoil mechanics with dyssynchrony parameters CURE , 4D–SDI  and C-SDI .EA patients  had significantly longer QRS duration  contains supplementary material, which is available to authorized users. Ebstein’s anomaly (EA) of the tricuspid valve is a rare but clinically important heart defect that accounts for approximately 0.5% of congenital cardiac malformations and occurs in about 1 per 200, 000 live births )1/2, where A [21 are the spatial and temporal sum of the zero and first order power terms, respectively. Measures range from CURE = 1 representing perfect synchrony and CURE = 0 for complete dyssynchrony [CURE was calculated as previously described : CURE = ynchrony .The prototype software 4D–LV-Analysis (TomTec Imaging Systems) uses three long-axis views and a short axis stack (1 short axis) to create a 4D representation of the LV volume changes during a cardiac cycle. End-diastolic and end-systolic endocardial borders were manually drawn in 2-, 3-, and 4-chamber views and automatically propagated onto the short axis views. Based on the outlined contours, a 4D model of LV contraction over one cardiac cycle was generated and automatically subdivided into 16 segments according to a modified 16-segment American Heart Association bulls-eye plot  and apical counter-clockwise rotation  were obtained using rotational displacement data of all 48 tissue points in corresponding slices. The distance (D) between basal and apical planes was calculated considering slice thickness and inter-slice gap. Torsion was defined as the difference of ∅basal and ∅ apical normalized to LV length: Torsion and torsion rates were calculated as described using Excel 2011 for Macintosh  . Basal cGlobal LV Torsion was calculated averaging subepicardial and subendocardial torsion. Peak systolic torsion rate (sysTR) and peak diastolic torsion rate (diasTR) were generated using the first derivative of torsion.p values <0.05 were considered statistically significant. For inter-observer variability, two independent observers (SU & TL) analyzed long and short axis stacks with CMR-FT and 4D–LV-analysis of 10 randomly selected patients with EA and 10 controls. Intra-observer variability was calculated after reanalysis of 10 randomly selected patients and 10 controls by the first observer (SU) six weeks after primary analysis. For both inter- and intraoberver variability the following parameters were assessed: 1. Intraclass Correlation Coefficents (ICC) 2. Coefficients of Variation (CoV) and 3. Bland-Altman-Analysis. Statistical analysis was performed using Microsoft Excel (Microsoft Corporation) and SPSS Statistics .Data are expressed as mean ± standard deviation. The Shapiro-Wilk-Test was used to test for normal distribution of the data. Since there was no normal distribution, data of EA and control group were compared using the Mann-Whitney-U test for non-parametric data. To represent potential relations between clinical parameters and obtained dyssynchrony- and torsion measures, Spearman’s correlation coefficients were calculated. All statistical tests with CMR-FT was successfully performed in all 31 patients and controls. The 4D–LV-Analysis was successfully performed in 28 patients and 31 controls. Three patients had to be excluded due to image artifacts and inability of the prototype software to create the 4 D volume curves. Patient characteristics can be found in Table Patients with EA showed significantly higher LV dyssynchrony in all CMR derived parameters compared to controls Table .In EA patients, dyssynchrony parameters C-SDI and CURE showed significant correlations with heart failure parameters NYHA and BNP, as well as the electrical dyssynchrony markers QRS and QTc as measures of depolarisation and repolarisation Table . LV 4D–SMoreover, we detected correlations of fRV ejection fraction (EF) with dyssynchrony markers 4D–SDI and C-SDI Whilst all torsion and recoil data showed a significant correlation with the LV dyssynchrony measure CURE, only sysTR and diasTR, respectively, showed correlation with C-SDI and 4D–SDI  or a more severe form of EA (as expressed by the R/L-Volume index) exhibited more intra-LV dyssynchrony.The deleterious effect of a malfunctioning or malformed RV on the LV has been described for various congenital cardiac malformations affecting primarily the right heart , includiThe indication and timing for surgery in the form of tricuspid valve repair or replacement is still a matter of debate in EA . Some ceFindings of this study suggest that the LV dyssynchrony described here may be a sign of impaired LV function in EA patients. Due to the relatively small sample size, we are unable to calculate cut-off values for measures of dyssynchrony , thus alerting the clinician to evaluate for tricuspid valve reconstruction, replacement or 1 and ½ repair (Glenn) in an individual patient. However, in combination with exercise testing and the total R/L index, the signs of LV dyssynchrony identified in this investigation could be a valuable tool in the detection of EA patients at risk for heart failure. This notion is underpinned by the correlation of dyssynchrony parameters with heart failure markers BNP and NYHA class observed in our study. Assenza’s observation that a fragmented and prolonged QRS complex  identifies patients with a more severe EA including more pronounced functional impairment and worse clinical profile , is keepIt is noteworthy that torsion and recoil mechanics appear to be preserved in EA, while they are frequently reduced in classic systolic heart failure conditions , 27, 28.This is a cross sectional study with a relatively small sample size and thus we cannot comment on changes in dyssynchrony as well as torsion/recoil markers and their prognostic impact over time. Correlation of synchrony with the other parameters studied is modest. Statistical significance may be impaired by small patient numbers. Due to the small sample size, multiple comparisons adjustments were not carried out, which is a statistical limitation of this study. However, the number of EA patients included is comparable with those reported in other published studies and due to the rarity of the disease inclusion of higher patient numbers is very difficult. A longitudinal and preferably multicentric study with more patients would be required to look at prognostic impact and possibly obtain higher statistical validity and correlation values. However, the present study can serve as a proof of principle that LV dyssynchrony is part of EA pathology and can be measured from CMR. Our sample size is comparable to that of previously published studies. Only 20% of EA patients in our cohort suffered from severe heart failure. Because all patients were included in a registry, we are optimistic that we could obtain the prospective data in the future.EA is characterized by LV intra-ventricular dyssynchrony, which is associated with heart failure and disease severity parameters. CMR derived markers of dyssynchrony can easily be obtained from routine CMR studies and may have a role in the assessment of deterioration of cardiac function, thereby carrying potential value for clinical decision-making.Additional file 1: Table S1.Table S2. Comparison of dyssynchrony parameters and torsion/ recoil parameters in a subgroup analysis of EA patients with ASD or previous surgery (“EA ASD/ operation”) vs. healthy controls (“controls”). Table S3. Interobserver analysis of differences in segmentation reproducibility for basal and apical slices. Table S4. Correlation of fRV ED and fRV stroke volume (fRV SV) with dyssynchrony parameters (DOCX 18 kb)Comparison of dyssynchrony parameters and torsion/ recoil parameters in a subgroup analysis of EA patients with ASD or previous surgery (“EA ASD/ operation”) vs. EA patients without ASD or previous surgery (“EA no ASD/ no operation”).


Mid-wall striae pattern late gadolinium enhancement (LGE) has been shown to independently predict future outcomes in patients with dilated non-ischemic cardiomyopathy (NICM). Standardized quantification tools are of particular interest for clinical translation of this novel imaging marker. However, signal intensity (SI) based threshold techniques, such as Signal Threshold versus Reference Mean (STRM) and Full Width at Half Maximum (FWHM), have been inconsistently applied and their performance in this population is unknown. The purpose of this study was to compare the accuracy of semi-automated LGE quantification techniques against expert-prescribed threshold assignment in patients with NICM.42, Circle Cardiovascular Inc.). Reference tissue regions of interest (ROI) were selected with careful attention to avoid artifact or blood pool. Peak SI in the remote tissue was automatically detected within remote tissue ROI by the software. Total septal LGE mass was compared to blinded expert segmentation of the same region using manual adjustment of the SI threshold. Bland-Altman analysis and intra-class correlation coefficients (ICC) were then applied.LGE images acquired using a 3.0T MRI system were assessed. Nineteen patients with NICM  and visually confirmed mid-wall septal LGE were studied. TI was manually adjusted to obtain optimal myocardial nulling (range: 280 to 340 ms). Total LGE mass in the septal region (defined as the region between and inclusive of RV insertion points) was quantified using 5 semi-automated techniques  threshold techniques). All analysis was performed using commercially available software , . STRM ≥ 5SD and FWHM techniques systematically underestimated septal LGE mass, and STRM ≥ 2SD technique over-estimated septal LGE mass (Figure STRM ≥ 3SD and PRT segmentation best approximate expert-defined septal LGE extent in patients with NICM. FWHM segmentation systematically underestimates and STRM ≥2SD overestimates septal LGE mass in this patient population.


Acute cellular rejection (ACR) may lead to compromised graft function after pediatric heart transplantation (HTX). The purpose of this study was to describe systolic ventricular function in pediatric HTX and its relationship with ACR.18 combined cardiac magnetic resonance (CMR)/endomyocardial biopsies were performed in 14 HTX patients ; 1.2 ± 1.3 years (12 days-5.0 years) after HTX). Biventricular function and left ventricular (LV) circumferential strain, rotation and torsion by CMR were compared to 11 controls. To adjust for repeated measurements in 2 HTX patients, Wald-testing and Bayesian modeling were used for statistical analysis.HTX patients showed reduced global LV circumferential strain , basal strain , mid-ventricular strain , apical strain , basal rotation , apical rotation  and LV torsion  when compared to controls.When comparing different degrees of ACR (Group A [grades 0-1 R]: 14 studies in 11 patients vs. Group B [grade 2R]: 4 studies in 3 patients), Bayesian modeling found high probabilities of 70-96% that RV ejection fraction, global strain, strain at all 3 LV levels and LV torsion were reduced in patients with grade 2 R rejection. Basal and apical rotation had highest sensitivity  and specificity  to discriminate between groups A and B.Pediatric HTX recipients, even in the absence of ACR, have decreased myocardial deformation by impaired LV circumferential strain, rotation and torsion. A further reduction is associated with ISHLT 2 R ACR. This pilot study suggests that myocardial deformation markers like basal and apical rotation may be non-invasive markers of significant ACR in pediatric HTX.


Right ventricular (RV) systolic performance is more difficult for evaluation compared to the left ventricle (LV). Despite differences in structure, RV myocardial fibers are in continuity with those of LV. The aim is assessment of the effects of LV wall motion abnormalities (WMA) on RV systolic function at rest and after stress.Fifty nine subjects, 15 with LV-WMA underwent dobuatmine stress echocardiography (DSE) studies using the usual protocol. Measurement of tricuspid annular plane systolic excursion (TAPSE), velocity (TASV), mitral annular plane systolic excursion (MAPSE) and velocity (MASV), were performed before and immediately after DSE studies.TAPSE was lower, in those with LV-WMA than in those without, both at rest 20.5 ± 4.8 mm versus 24.9 ± 4.7 mm, P = 0.015 and after DSE studies, 21.5 ± 5.6 mm versus 27.65 ± 5.7 mm, P = 0.005. DSE studies did not change TAPSE significantly in the presence of LV-WMA. TASV at rest in those with LV-WMA was 16.5 ± 2.7 cm/sec and similar to that in those without, 17.6 ± 3 cm/sec. In both groups the velocity increased after DSE studies, 23.25 ± 7.5 cm/sec, P = 0.01 with LV-WMA, and 27.5 ± 6 cm/sec, P = 0.0005, without LV-WMA. Despite similar TASV at rest, the TAPSE/TASV ratio, indicating duration of shortening, was lower (124 ± 21 msec) in subjects with of LV-WMA, than in those without (145 ± 27 msec), P = 0.0065, implying increased after load for RV longitudinal shortening in the presence of LV-WMA.TAPSE is lower at rest and after DSE studies in subjects with LV-WMA than in subjects without; however, DSE studies increase TPASE only in the absence of LV-WMA. TASV increases after DSE studies and is similar at rest in both groups with or without LV-WMA. It seems that LV-WMA increases after load to RV longitudinal motion. Evaluation of left ventricle (LV) systolic function by trans-thoracic echocardiography is standardized and widely applied. Previously, the dynamics of changes in longitudinal LV systolic function induced by stress have been reported . On the Longitudinal systolic performance abnormalities precede LV systolic radial abnormalities . TricuspFifty eight patients, 29 women, age 60.3 ± 13.4 years, were prospectively evaluated for the presence of coronary artery disease. Fifteen of the subjects had LV-WMA at rest. Patients with pulmonary disease, right heart disease, valvular heart disease, atrial fibrillation or other rhythm disturbances and acute coronary syndrome within 3 months were not included. All underwent dobutamine stress echocardiography (DSE) studies using the usual protocol and measurement of RV and LV systolic function before and after DSE studies.The protocol of dobutamine infusion consisted of 3 minute stages for each dose, starting with 5 µg/kg/min and increasing to 10, 20, 30 and 40 µg/kg/min. If end-points did not occur or 85% of the age adjusted heart rate was not achieved, 0.25 mg atropine was injected every 2 minutes up to 1 mg or until the target heart rate was achieved. Blood pressure and 12 lead electrocardiograms were recorded at rest and throughout the DSE study. Horizontal or down-sloping > 1 mm ST-segment depression at 0.06 sec after the J point were considered as evidence for myocardial ischemia.Images were obtained while the patients in the left lateral decubitus position. A standard commercial Siemens, Acuson Sequoia echocardiography system, California, equipped with 3.5 MHZ transducers was used. All patients had complete Doppler echocardiographic studies before DSE. Parasternal long axis and short axis, as well as, apical 4-chamber and 2-chamber views were recorded at rest, low dose dobutamine infusion, peak exercise and in the recovery period. Digital images were stored on magneto-optic discs for later off-line analysis. In addition super VHS videotape recordings were performed throughout the studies.Segmental LV wall motion analysis was performed using 16-segment model . RegionaMeasurements of TAPSE (mm) using M-mode echocardiography at the lateral border of the tricuspid annulus from apical four chamber view, and TASV (cm/sec) from the same approach and site using pulsed-wave tissue Doppler imaging were performed. Mitral annular plane systolic excursion (MAPSE) from M-mode echocardiography (mm) of the mitral annulus at the lateral and septal borders, and mitral annular systolic velocity (MASV) from the same sites using pulsed-wave tissue Doppler imaging (cm/sec) were performed. Ratios of TAPSE/MAPSE and TASV/MASV were calculated. Measurements and calculations were performed at rest and immediately after DSE.Mean values and standard deviation of TAPSE, MAPSE, TASV, MASV and ratios were calculated for all subjects. Student t-test assuming unequal variances, was performed; P < 0.05 was considered significant. Comparison was performed between subjects with and those without LV-WMA. Comparisons between RV and LV findings were performed using student t-test.All subjects underwent DSE studies safely and uneventfully. In subjects without LV-WMA, heart rate increased from 70.7 ± 10 bpm to 138 ± 11.8 bpm, P < 0.00001, and in subjects with LV-WMA increased from 74.2 ± 17.6 bpm to 130.9 ± 15.6 bpm, P < 0.00001. Heart rate was similar between groups both at rest and after DSE studies. Systolic blood pressure increased from 138 ± 7 mmHg to 162 ± 9 mmHg, P < 0.0001, in all subjects without significant inter-group difference.In 26 subjects WMSI was 1 at rest and did not change after DSE studies, while in 18 subjects WMSI was 1 at rest and increased to 1.12 ± 0.14 after stress. In 15 subjects WMSI at rest was 1.36 ± 0.34 and increased to 1.47 ± 0.32 after DSE studies.TAPSE and TASV were similar at rest and after DSE in normal subjects and in those with LV-WMA only after DSE . TherefoIn subjects with LV-WMA at rest, TAPSE was lower than in those without resting LV-WMA, both at rest and after DSE, indicating lower RV systolic function . While iRV longitudinal systolic function as measured by TAPSE was coordinated with LV septal and lateral excursions both at rest and after DSE studies. Thus, TAPSE/MAPSE did not change after DSE studies . MoreoveIn addition, TASV was coordinated with that of LV. Presence or absence of LV-WMA did not affect this inter-ventricular coordination both at rest and after DSE studies .As depicted in In this study it was shown that RV systolic function at rest and after DSE as measured by TAPSE was lower in those with LV-WMA at rest compared to those without. In addition, RV systolic function reserve as evaluated by the increase in TAPSE after DSE in normal subjects, was abolished in the presence of resting LV-WMA.As we found, measurement of TAPSE is feasible and easy to obtain, and the values are similar to those found in a previous study which proved the accuracy of this parameter in assessing RV systolic function compared to other parameters like fractional area change . AnotherTo answer the question why RV systolic function is affected by LV systolic function abnormalities, understanding the anatomy and relation of the myocardial fibers of both ventricles is essential. Thus, contrary to the left ventricle which is composed of three myocardial fiber layers-superficial obliquely directed fibers, middle circumferentially directed fibers and deep inner layer with longitudinal fibers; the RV wall is composed only of two myofiber layers . The dirA previous study found that TASV correlated with fractional area change of RV and with TAPSE . Yet, anWhy LV-WMA did not affect TASV significantly and yet it decreased TAPSE? In fact, TAPSE is the integral of velocity (TASV) upon time. Despite similar heart rates in the presence or absence of LV-WMA, the ratio of TAPSE/TASV was higher in the absence of LV-WMA. This time index implying longer contraction time of RV myocardial fibers in the absence of LV-WMA can be explained by higher afterload to RV contraction in the presence of LV-WMA (similar to friction effects with higher deceleration and thus more rapid decrease of velocity). The increase in RV afterload interrupts shortening of RV myocardial fibers prematurely. It seems that regional LV-WMA, by changing geometry may lead to alterations in RV myocardial fibers, and thus may affect contraction period of RV. Increase in pulmonary vascular resistance is another factor which may contribute to these results, however pulmonary hypertension was not found in these patients, and it seems unlikely in this study population. Since TASV was similar in both groups, it can be deduced that LV-WMA did not affect contraction of RV myocardial fibers. Thus, RV contractility seems similar while the afterload impeding contraction of RV myocardial fibers may explain the findings in our study. Since RV size and shape were normal and similar in all subjects, and no significant tricuspid regurgitation was observed, it seems that preload did not affect the results of our study.The increase in heart rate during DSE studies, significantly shortened effective average TAPSE displacement time. After DSE studies no significant difference in TAPSE/TASV time index was observed between subjects with and without LV-WMA. It seems that the increase in TASV after DSE contributed to the larger TAPSE post DSE in subjects without LV-WMA.Changes of TAPSE and TASV paralleled changes in MAPSE and MASV, implying the dependence of RV longitudinal systolic function and reserve on the status of LV. There was no significant difference in the ratio of TAPSE/MAPSE between the groups at rest and after DSE. In addition, DSE studies did not change this ratio compared to rest in both groups. The ratio TASV/MASV behaved in a similar fashion to TAPSE/MAPSE ratio, and thus emphasizing the interdependence of RV and LV.In addition to the interventricular septum and pericardium, the continuity between RV and LV myocardial fibers contributes to ventricular interdependence . DespiteTAPSE and TASV were similar at rest and after DSE in normal subjects and in those with LV-WMA only after DSE. Therefore, in further analysis, both groups were evaluated as one group and were compared to patients with LV-WMA at rest. It seems that, the WMSI which equaled 1 at rest and increased only to 1.12 ± 0.14 after DSE was of small magnitude and therefore the studied RV parameters were normal. It remains to be shown that if WMSI after DSE was higher, the RV parameters would behave abnormally.Longitudinal RV systolic performance is related to LV performance, and thus TAPSE is decreased in the presence of LV-WMA. TAPSE increases after DSE studies, however, TPSAE reserve is negligible in the presence of LV-WMA. TASV increases after DSE studies, but was similar in the presence or absence of LV-WMA wall motion abnormality. LV-WMA increases afterload to RV longitudinal systolic performance. Afterload to septal longitudinal motion is higher than to lateral LV and RV systolic motion.


This study aimed to investigate the advantages of recently developed cardiac imaging techniques of fat–water separation and feature tracking to characterize better individuals with chronic myocardial infarction (MI).LV) and radial (ErrLV) strain were calculated using dedicated software . The extent of global scar was measured in LGE and fat–water separated images to compare conventional and recent CMR imaging techniques.Twenty patients who had a previous MI underwent CMR imaging. The study protocol included routine cine and late gadolinium enhancement (LGE) technique. In addition, mDixon LGE imaging was performed in every patient. Left ventricular (LV) circumferential (Eccp = 0.005). There was no significant difference in EccLV or ErrLV between myocardial segments containing fibrosis only and fibrosis with fat. However, EccLV and ErrLV values were significantly higher in myocardial segments adjacent to fibrosis with fat deposition than in those adjacent to LGE only.The infarct size derived from conventional LGE and fat–water separated images was similar. However, detection of lipomatous metaplasia was only possible with mDixon imaging. Subjects with fat deposition demonstrated a significantly smaller percentage of fibrosis than those without fat (10.68 ± 5.07% vs. 13.83 ± 6.30%; Advanced CMR imaging ensures more detailed tissue characterization in patients with chronic MI without a relevant increase in imaging and post-processing time. Fatty metaplasia may influence regional myocardial deformation especially in the myocardial segments adjacent to scar tissue. A simplified and shortened myocardial viability CMR protocol might be useful to better characterize and stratify patients with chronic MI. The prognosis of subjects who survived acute myocardial infarction (MI) has substantially improved in recent decades . MyocardA recent observational cardiac magnetic resonance (CMR) study reported that fat deposition can be detected in up to 78% of individuals who experienced MI . LipomatValidated CMR technique using a three-dimensional (3D) single breath-hold ECG-gated magnetization prepared multiecho Dixon (mDixon) sequence has gained increased interest over recent years. Fat-only images derived using this technique can be used to detect and quantify cardiac adipose tissue . The proThe CMR feature tracking (CMR-FT) technique provides information about myocardial mechanics. Myocardial strain and strain rate can be derived from conventional balanced steady state free precession (bSSFP) cine images and can be used to assess myocardial function . Recent We conducted this study to determine the advantages of recent CMR imaging techniques. We assessed changes in myocardial tissue after MI using mDixon technique. In addition, we investigated changes in global and regional myocardial deformation in patients with lipomatous metaplasia using CMR-FT.We retrospectively enrolled 20 subjects with chronic MI  to assess global and regional cardiac function, myocardial tissue composition, viability, and new myocardial ischemia. The medical history of the participants was obtained from medical records. The study complies with the Declaration of Helsinki and was performed in accordance with local law. Informed consent was obtained from all patients.All CMR images were acquired using 1.5 (Achieva) or 3 T  MRI scanners with a 32-channel cardiac surface coil in supine position. All study participants were scanned using an identical comprehensive imaging protocol.3 , and 30 phases per cardiac cycle; for the 3 T scanner: TR = 2.9 ms, TE = 1.45 ms, flip angle = 45°, acquisition voxel size = 1.9 × 1.9 × 8.0 mm3 , and 30 phases per cardiac cycle.The study protocol included initial scouts to determine cardiac imaging planes. Cine images were acquired using ECG-gated bSSFP sequence with multiple breath-holds at end-expiration in three left ventricular (LV) long-axis  planes. The ventricular two-chamber and four-chamber planes were used to plan the stack of short-axis slices covering the entire LV. The following imaging parameters were used. For the 1.5 T scanner: repetition time (TR) = 3.3 ms, echo time (TE) = 1.6 ms, flip angle = 60°, acquisition voxel size = 1.8 × 1.7 × 8.0 mm®, Bayer Schering Pharma AG, Berlin, Germany). A Look-Locker sequence was acquired to determine the inversion time to null the signal of the LV myocardium. A 3D inversion recovery fat saturated spoiled gradient echo sequence was used to detect scar tissue in three LV long-axis and short-axis orientations  = 2.2; for the 3 T scanner: TR = 3.2 ms, TE = 1.62 ms, flip angle 15°, acquisition voxel size 1.5 × 1.5 × 10.0 mm3, SENSE = 2.2. The breath-hold time varied from 12 to 16 s, depending on anthropometrics. Single 3D long-axis scan was acquired during one breath-hold. Two breath-holds were required to acquire full 3D short-axis scan.The LGE images were obtained 10 min after the injection of 0.15 mmol/kg gadobutrol  = 2.2; for the 3 T scanner: TR = 3.8 ms, TE1 = 1.3 ms, TE2 = 2.4 ms, flip angle = 12°, voxel size 1.7 × 1.7 × 5.0 mm3, SENSE = 2.2. In-phase  sequence was used for fat water separation imaging. The following sequence parameters were used. For the 1.5 T scanner: TR = 4.7 ms, TE1 = 1.5 ms, TE2 = 3.0 ms, flip angle = 15°, voxel size 1.6 × 1.6 × 5.0 mmAll images were analyzed offline using commercially available software  in accordance to a recent consensus document for quantification of LV function and mass using CMR . LV end-The endocardial and epicardial contours drawn on cine images were transferred into LGE images. The presence and extent of LGE were quantified using the signal threshold versus reference mean (STRM) >3 standard deviations (SD) method as it provides the greatest accuracy with acceptable reproducibility compared with other signal intensity threshold techniques . All algThe endocardial and epicardial contours were similarly transferred into mDixon images using the same program. The fat deposition volume and mass were calculated using the same signal intensity threshold level (>3 SD) in the fat-only images. The extent of fat was classified as subendocardial, subepicardial and transmural. Fibrosis volume and mass were calculated using the identical approach in the water-only images. Additionally, the extent of LGE was assessed in the in-phase mDixon images. The location of LGE and fat deposition was defined using a standard American Heart Association (AHA) 17-segment model  depending on their distribution, and categorical variables were described as total number (percentage). Differences in normally and non-normally distributed continuous variables were established using an unpaired Student In total, 20 patients (10 with fat deposition and 10 without) were included in our study. All participants were scanned using two different magnetic field strength MRI scanners (1.5 and 3 T) at random without any specific selection. All patients without fat deposition were imaged by the 1.5 T machine, whereas three (30%) patients with fat deposition underwent CMR imaging on the 3 T scanner. There was no significant difference between the groups with respect to subject age, gender, body mass index, body surface area, or infarct age. Figure p = 0.168). Subjects with fat deposition had significantly lower cardiac index compared with those without fatty metaplasia .In our study, LV EDV, LV EDV index, LV ESV, LV ESV index, LV mass, LV mass index, and cardiac output were similar in both groups. A trend of lower LV EF was seen in patients with detected lipid accumulation, but the difference did not reach statistical significance .Among the total of 340 segments analyzed in this study, 91 (26.8%) had LGE and 31 (9.1%) had fat deposition. Twenty-seven (7.9%) segments had both LGE and fat deposition, while 64 (18.8%) segments had LGE and no fat deposition. Of 170 segments analyzed in the fat deposition group, four (1.2%) segments had fat deposition without LGE, but all these segments were adjacent to myocardial segments with LGE.Of 20 infarcts, 18 (90%) were transmural and the remaining two (10%) were subendocardial. All patients with fat deposition had transmural myocardial infarctions. Of 10 transmural infarcts in the fat deposition group, two (20%) had fat deposition in the subendocardial layer and two (20%) in the subepicardial layer of myocardium. The remaining six (60%) patients showed transmural fat deposition.p = 0.048). Significantly higher LGE mass was found in patients with fat deposition , as well as a larger percentage of LGE . The fibrosis mass and percentage to myocardial mass were similar in both groups . The percentage of infarcted myocardium was also similar for both imaging techniques (p = 0.807) . Detection of fat deposition was only possible with fat–water separated (mDixon) imaging. Fat deposition mass and percentage to LV myocardial mass in patients with lipomatous metaplasia were 5.17 ± 2.61 g and 4.83 ± 2.33%, respectively  images  Fig. . IndividSeven (70%) patients with fat deposition detected using mDixon imaging had dark zones in the myocardium in bSSFP cine images due to fat tissue induced chemical-shift artifacts.As described in the methods, analysis of segmental myocardial deformation was performed using an AHA 16-segment model (16 segments in 20 patients resulting in 320 segments).Among a total of 320 segments analyzed, 85 (26.6%) had LGE and 31 (9.7%) had fat deposition. Twenty-seven (8.4%) segments had both LGE and fat deposition, while 58 (18.1%) had LGE and no lipomatous metaplasia. Four (1.3%) segments had fat deposition without LGE.LV and ErrLV values of segments with LGE when compared with segments of remote myocardium . There was no significant difference in EccLV or ErrLV between segments containing fibrosis only and fibrosis with fat deposition  . Interestingly, there were significantly higher EccLV and ErrLV values of myocardial segments adjacent to segments containing fibrosis and fat deposition than in those adjacent to segments containing fibrosis only   LGE imaging technique is unable to discriminate fat from scar tissue.The infarct size calculated using mDixon images is similar to that estimated in routine LGE images.Lipomatous metaplasia is found only in myocardial segments with or directly adjacent to infarcted myocardium.Fat deposition does not influence regional myocardial function in segments with LGE, but has a positive effect on myocardial deformation in segments adjacent to scar tissue.In this single center study we noninvasively assessed myocardial tissue characteristics in patients with old MI using conventional and newly developed CMR imaging—mDixon technique. We assessed the relationship between fatty metaplasia and global as well as regional cardiac function parameters. Our study is based on intra-individual and inter-individual comparison and indicates several important findings:A number of case reports have been published that describe fat deposition in patients with chronic MI –21. ManyA number of CMR techniques may be used to detect lipid accumulation within the myocardium. A larger amount of fat tissue is visible in currently used bSSFP images as dark zones encompassing the borders between fat- and water-containing tissue due to chemical-shift artifacts . We obseA method of fat and water separation based on proton chemical shift imaging was first described by Dixon . Dixon sWe demonstrated that detection of fatty metaplasia only is possible with fat–water separated imaging. This has also been shown in previous studies. Furthermore, we showed that infarct size as determined with the mDixon technique is similar to the infarct size as estimated in routine LGE images. On the basis of our findings we propose an updated and shortened imaging protocol for patients with chronic MI Fig.  using mDThe ability to quantify diffuse myocardial tissue alterations using noninvasive imaging is of considerable clinical interest. Parametric mapping techniques allow signal quantification by using T1 and T2 relaxation times that are displayed as color maps to facilitate visual assessment. The native T1 is increased with myocardial edema, fibrosis or deposition of amyloid and is reduced in lipid accumulation, Anderson–Fabry disease or iron overload . Post-coSince fatty metaplasia was found only in segments within or directly adjacent to the infarct area, one might infer that the healing process is a precursor of lipid accumulation . The stuCMR-FT as a novel tissue tracking technique became available in 2009 . The advIt has been noted that myocardial segments with scar show lower deformation values than remote myocardium . NotwithEarlier studies indicated that myocardial fibrosis is the primary structural observation associated with ventricular tachycardia . HoweverSeveral limitations of the current study should be mentioned. First, the population of this study was relatively small and there was a wide variety of MI characteristics in terms of age, treatment, and location. Subjects of the study were mostly long-term survivors with preserved LV systolic function. Second, the risk factors leading to fat deposition have not been investigated in this study.In this single center study we assessed characteristics of myocardial tissue in patients with chronic MI using mDixon CMR imaging and compared it with routine LGE technique. Fat–water separated imaging ensures more detailed tissue characterization in patients with chronic MI, without a relevant increase in imaging and post-processing time. Fatty metaplasia may influence regional myocardial deformation especially in myocardial segments adjacent to scar tissue. However, larger studies are necessary to prove this finding. These achievements may help to identify patients at risk for future cardiac events. A simplified and shortened myocardial viability CMR protocol might be useful to better characterize and stratify patients with chronic MI.


During a preoperative cardiac assessment, a 57-year-old asymptomatic female, withoutknown cardiac risk-factors, was found to have LBBB on ECG. Echocardiography revealeddilated cardiomyopathy. To rule-out coronary artery disease, coronary CT-angiography wasperformed and showed no significant coronary obstruction.For further evaluation, a cardiac magnetic resonance (CMR) study was performed. A focalarea of fatty infiltration was seen in the left ventricular (LV) apex extending from thesubendocardial to the subepicardial surfaces  and 1B. A follow-up CMR study after 18 months - using 3 Tesla magnet - showed no significantchanges of fat distribution within the LV, and a mild reduction of LV systolic function(ejection fraction =45%) that was similar to the initial study -I.There are few differential diagnoses. Firstly, cardiac lipoma, which is usuallywell-defined and well-encapsulated, and generally produces compression on adjacentcardiac structures. Secondly, fatty deposition following MI is associated withmyocardial thinning and scarring on DHE images. Lastly, arrhythmogenic left ventricularcardiomyopathy is a substrate for ventricular arrhythmias and usually involvesinterventricular septum.Isolated fatty LV cardiomyopathy is an uncommon clinical entity, and it could beunder-diagnosed. With recent technological advancements in CT and MRI, more cases can bedetected and investigated.


Until now, no consensus is reached for the standardized assessment and quantification of extent and severity of myocardial ischemia and necrosis by cardiac magnetic resonance imaging (CMR). However, there is a good evidence base suggesting that these parameters might ameliorate established risk prediction models and thus might lead to an improved management of patients with stable coronary artery disease (CAD). Objective of this study therefore is to elaborate an easy-to-use algorithm for the quantification of ischemia and necrosis and to validate the obtained data in a large cohort of CAD patients.Patients with known or suspected CAD referred for adenosine-perfusion CMR were consecutively and prospectively enrolled. Examinations were conducted on a 1.5 Tesla whole-body scanner  using a 5-element phased array surface receiver coil. All patients underwent standard first-pass perfusion imaging  under adenosine infusion for the detection of myocardial ischemia and late gadolinium enhancement (LGE) imaging  for the assessment of myocardial necrosis. Based on these sequences, ischemia and necrosis were quantified using a novel algorithm.Primary endpoint was defined as combination of cardiac death, non-fatal myocardial infarction and stroke. Several risk prediction models containing clinical and CMR parameters were built and analyzed with regard to correct risk stratification and endpoint prediction.The study cohort consisted of 845 patients. Median follow-up was 3.66  years. During this time, 61 primary endpoints occurred. Cutoff values for myocardial ischemia and LGE could be defined . A risk prediction model containing this information proved to be superior in comparison to models based on conventional CMR features .Myocardial ischemia and necrosis above the defined cutoff values are strongly associated with major clinical endpoints. Quantification of these parameters provides additive information and leads to improved risk stratification.


Cardiac PET quantifies stress myocardial blood flow (MBF) and perfusion reserve (MPR), while ECG-gated datasets can measure components of ventricular function simultaneously. Stress MBF seems to outperform MPR in the detection of significant CAD. However, it is uncertain which perfusion measurement is more related to ventricular function. We hypothesized that stress MBF correlates with ventricular function better than MPR in patients studied for suspected myocardial ischemia.We studied 248 patients referred to a rest and adenosine-stress Nitrogen-13 ammonia PET. We performed a multivariate analysis using systolic function , diastolic function , and synchrony (Entropy) as the outcome variables, and stress MBF, MPR, and relevant covariates as the predictors. Secondarily, we repeated the analysis for the subgroup of patients with and without a previous myocardial infarction (MI).P < .001) and ventricular function. This was stronger than the one for MPR (P = .063). Sex, age, diabetes, and extent of previous MI were also significant predictors. Results were similar for the analyses of the 2 subgroups.166 male and 82 female patients  were included. 60% of the patients presented hypertension, 57% dyslipidemia, 21% type 2 diabetes mellitus, 45% smoking, and 34.7% a previous MI. Mean stress MBF was 1.99 ± 0.75 mL/g/min, MPR = 2.55 ± 0.89, LVEF = 61.6 ± 15%, MFR/3 = 1.12 ± 0.38 EDV/s, and Entropy = 45.6 ± 11.3%. There was a significant correlation between stress MBF  contains supplementary material, which is available to authorized users. Cardiac positron emission tomography (PET) imaging has developed as an important adjuvant for diagnostic, prognostic, and therapeutic evaluation in the evolving profile of coronary artery disease (CAD), and is currently the reference technique for the quantification of myocardial perfusion in absolute terms.Recently, it has been suggested that stress MBF may perform better than MPR in the detection of flow-limiting CAD. This may be especially true in populations without previously known CAD or in conditions that show a higher rest MBF such as women, older patients, or those with arterial hypertension.Furthermore, ECG-synchronized (gated) PET datasets can be simultaneously acquired offering the possibility to assess three areas of ventricular function, namely: systolic  and diastolic (i.e. filling) function,Therefore, the aim of the present study was to evaluate whether stress MBF or MPR, as measured by PET myocardial perfusion imaging, better correlates with ventricular function in the general population of patients with known or suspected CAD. Secondarily, we explored the relationship of stress MBF and MPR with ventricular function in patients with and without a previous myocardial infarction (MI) as it is known that there are differences in ventricular perfusion and function dynamics.A supplementary analysis for subgroups of interest within patients without a previous MI  was also conducted.A retrospective study was conducted including 248 patients referred to the PET/CT Unit at the National Autonomous University of Mexico in Mexico City by their cardiologist for the evaluation of suspected myocardial ischemia. Demographic and clinical data were retrieved through the electronic patient archive system. Several clinically relevant confounders were included in this study: sex, age, body mass index (BMI), hypertension, dyslipidemia, type 2 diabetes mellitus (DM), smoking habit, and semiquantitative perfusion scores (see ahead). Ethical approval was obtained for the conduction of the study from the local institutional ethics committee.PET images were acquired on a whole-body 64-slice PET/CT scanner . PET data were acquired in 3-D list mode. Patients were studied after an overnight fast, and all refrained from caffeine-containing beverages or theophylline-containing medications for 24 hours before the study. Myocardial perfusion was assessed at rest and during vasodilator stress with adenosine and Nitrogen-13 ammonia as the perfusion radiotracer. Two CT-based transmission scans  were obtained before the rest perfusion studies and after the stress perfusion studies with normal breathing for correction of photon attenuation for PET. The registration of the CT attenuation map with the PET images was verified visually by an experienced technologist and alignment was corrected if necessary by manual 3-D translation. Regional myocardial perfusion was first assessed during rest using 740 MBq of Nitrogen-13 ammonia. Rest imaging extended for 10 minutes and began a few seconds before the injection. The radiotracer was administered as a single peripheral intravenous bolus (3-5 seconds) followed by a 10-mL saline flush. Thirty minutes later, a pharmacological stress test was performed, beginning with the injection of adenosine during a 6-minute period (140 mg/kg per minute). A second dose of 740 MBq of Nitrogen-13 ammonia was injected at the third minute of the adenosine infusion. Stress images acquisition was started a few seconds before the radiotracer injection. Sixteen dynamic frames were reconstructed . Standard reconstruction (2-D attenuation-weighted OSEM) was used with 3 iterations and 14 subsets and 3-D postfiltering with a 5-mm Gaussian kernel filter. Transverse data were reformatted to a 168×168×47 matrix with 2 mm pixels for each dynamic frame.Images were interpreted semiquantitatively using the standard American Heart Association 5-point scoring system Left ventricular contours and input function regions were obtained automatically allowing minimal observer intervention in QPS software package . Dynamic myocardial samples were obtained from the polar map by analyzing all time frames within the fixed left ventricular contour boundaries. Quantitative rest and stress MBF values (mL/g/minute) were computed for each sample on the polar map as described previouslyECG-gated stress images were analyzed with the QGS software package .Systolic function was evaluated through left ventricular ejection fraction (LVEF) (% of the end-diastolic volume ejected) using the average time-volume curves. Next, diastolic function was evaluated with the mean filling rate during the first third of diastole (MFR/3) as a surrogate marker. MFR/3 was obtained from the first derivative of the left ventricular time-volume curve and expressed in end-diastolic volumes per second (EDV/s) as it is adjusted to the ventricle dimensions on a patient-by-patient basis.Finally, ventricular synchrony was evaluated through Entropy, which is a measurement of uniformity of the onset and progression of wall motion throughout the cardiac cycle.t tests.All continuous variables are described as mean ± standard deviation, and categorical variables are expressed as frequencies with percentages. Between-group comparisons were made using independent samples F statistic. Further, the multivariate analyses were repeated including the same independent and dependent variables for patients with and without imaging evidence of a previous MI. Additionally, the effect sizes for the predictors (η2) are reported and graphically depicted.The biserial correlations (using Pearson’s correlation coefficient) between LVEF, MFR/3, and Entropy were evaluated. Next, a general multivariate analysis of covariance (MANCOVA) was performed including sex, age, BMI, hypertension, dyslipidemia, type 2 DM, smoking habit, SRS, SSS, stress MBF, and MPR in the model as the independent (i.e. predictive) variables, and LVEF, MFR/3, and Entropy as the dependent (i.e. outcome) variables. The independent significance of the included predictors was tested using Pillai’s trace criterion with an approximate Finally, supplementary analyses were performed in both female and hypertensive patients without a previous MI.P-value of <0.05 was considered statistically significant.All statistical analyses were performed with SPSS . A Baseline characteristics, semiquantitative, quantitative perfusion, and ventricular function data are presented in Table Differences were found in clinical characteristics, perfusion , and ventricular function parameters  between patients with and without MI. There was a higher, although not significant, rest MBF in patients without MI.The corresponding data for the subsample of women and patients with arterial hypertension can be found in Supplementary Material—Online Resource 1 and showed comparable distribution of baseline characteristics with the exception of a higher proportion of asymptomatic patients and a lower proportion of previous revascularization procedures. Also, there was a comparable rest and stress MBF in women and hypertensive patient groups.We documented significant and strong correlations between systolic, diastolic, and synchrony function variables. Pearson’s correlation coefficients showed significance between LVEF and MFR/3, LVEF and Entropy, and MFR/3 and Entropy. These results are depicted in the correlation matrix shown in Table P < .001, η2 = 0.111) of the ventricular function , while MPR showed only a trend toward significance (P = 0.063). From the other clinically relevant variables included in the model, sex (P = .003), age (P = .004), type 2 DM (P = .025), and SRS  were also found to be significant predictors , while MPR was not (P = .27). In this analysis, sex and BMI were also significant predictors . Similar results were obtained in the analysis of patients with evidence of a previous MI: stress MBF (P = .022), MPR (P = .090), and SRS (P = .004). These results are shown in more detail in the Supplementary Material—Online Resources 2 and 3. The magnitude of the effect sizes for the primary and secondary analyses is depicted in Figure The secondary exploratory multivariate analysis for patients without a previous MI (n = 162) again showed that stress MBF was significantly associated with ventricular function  considering the amount of relevant variables in the other analyses. As for noninfarcted patients with hypertension (n = 101), results were similar to those in the primary and secondary analyses .A supplementary follow-up univariate analysis divided per measurement of ventricular function can be consulted in Supplementary Material—Online Resources 5 through 7.In the present study, we have shown that stress MBF correlates better that MPR with ventricular function in a population of patients with suspected ischemia using an integral statistical approach. By inputting both quantitative perfusion measurements (i.e. stress MBF and MPR) in the analyses, we have aimed to compare their relative importance based on their independent association with ventricular function.In the first part of the study, we documented differences between important subgroups concerning the presence or the absence of a previous MI. Results have confirmed important differences in ventricular perfusion and several components of ventricular function as well as in clinical profile between these two groups of patients. Patients with evidence of a previous MI had a higher prevalence of type 2 DM which adds to their prognostic profile. Interestingly, they were more symptomatic and showed slightly more ischemic burden overall. As expected, a worse ventricular function profile was found. However, not only scar but also perfusion seems to play a role in their functional status.A close statistical relationship between systolic, diastolic, and synchronic ventricular function was observed. In the clinical scenario, functional measurements may individually serve at different points of the spectrum of severity of CAD. Nonetheless, they also provide, in compound, a proxy for the overall status of ventricular function since in reality they are probably not modified independently. Still, further research is needed to define the optimal measurements of diastolic function and synchrony, as well as their particular normal values in different clinical scenarios evaluated with PET imaging.Next, we documented that stress MBF is consistently better correlated to ventricular function than MPR as evidenced by their significance values and moderate effect sizes in the multivariate models Figure , indepenThe significant association of stress MBF with ventricular function was sustained in the supplementary analysis of patients with hypertension and without previous MI. These results suggest a greater relevance of stress MBF, rather than MPR, in the profile of patients who may benefit from its evaluation in routine clinical practice. Moreover, considering the use of stress MBF as an alternative to MPR may be of benefit considering patient safety for the evaluation of ischemic burden. In this sense, acquisition times and radiation doses can be reducedWe have found other significant predictors of ventricular function, although not as strong as stress MBF, namely: sex, age, and type 2 DM. These results support previous studies describing sex-based systolic function differences, a progressive decline of diastolic function associated with age,The clinical use of quantitative perfusion goes beyond diagnosis. Risk stratification and prediction of CAD-related outcomes are of major interest in noninvasive cardiac imaging due to the major burden that cardiovascular disease represents.A previous report from our groupWe believe that further investigation will optimize the application of cardiac PET by exploring the clinical value of combined perfusion-function measurements which may offer more integral gauges of cardiac health.This study demonstrated that peak-stress MBF correlates with ventricular function  better than MPR and independently from relevant covariates. Additionally, the present work showed that the described greater correlation of stress MBF with ventricular function is sustained in the patients with and without a previous MI and in noninfarcted patients with arterial hypertension.One of the characteristics of our study is that we have approached a fairly heterogeneous population. Although this potentially yields difficulty in addressing multivariate relations, we believe that this approach rather provides a broad view of these complex relations in the setting of the day-to-day reality of specialized cardiovascular imaging centers. Another potential limitation of our study, especially for the assessment of rather novel diastolic function parameters such as MFR/3, is that the analysis of the gated datasets was performed with a binning of 8 frames per cardiac cycle. Although this may not be optimal, there are a number of studies which have demonstrated that the obtained assessment and derivation of the time-volume curves from 8 frames is comparable to SPECT reconstructions made using 64 frames. In the future, complementary echocardiographic evaluation can be useful. Yet, another limitation is the lack of regional perfusion analysis. Although of interest, we aimed to account for the global perfusion status and its influence on the global ventricular function. Therefore, the influence of specific regional measures cannot be evaluated from this study alone.Stress MBF is better correlated with ventricular function than MPR, as evaluated by Nitrogen-13 ammonia PET, independently from other relevant cardiovascular risk factors and clinical covariates. This relationship between coronary vasodilatory capacity and ventricular function is sustained across groups with and without a previous MI. Further research in the clinical utility of PET evaluation of stress MBF and its prognostic value is warranted.Supplementary material 1 (DOCX 267 kb)Supplementary material 2 (PPTX 1689 kb)Below is the link to the electronic supplementary material.


Cardiac magnetic resonance (CMR) allows the combined evaluation of myocardial perfusion status and viability in the same examination. Novel methods for high-resolution quantiative analysis of myocardial perfusion have rencently been described. High-resolution perfusion avoids spatial averaging and potentially enables a more accurate assessment of total inducible ischaemic burden. The simultaneous analysis of high-resolution late gadolinium enhancement images (LGE) allows excluding areas with overt ischaemic scar from quantitative perfusion analysis. This is potentially relevant to the estimation of the ischaemic burden, since areas of scar have can result in false-positive perfusion findings. The aim of this study was to test the feasibility of combined high-resolution assessment of perfusion and late enhancement, and to assess the potential of this novel approach to provide a more accurate estimation of the ischaemic burden in patients with coronary artery disease.20 patients with known CAD and previous myocardial infarct referred for stress perfusion CMR due to new onset of angina were included. All patients underwent rest and adenosine stress first-pass perfusion at 3T (Philips Achieva) using a high-resolution kt turbo field echo sequence and a dual bolus approach . LGE images were acquired 15 minutes after the rest injection of Gd. Quantiative perfusion analysis was performed using validated high-resolution deconvolution analysis. LGE analysis was performed using conventional semi-quantitative analysis . Stress and rest myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and total LV ischaemic burden (MPR threshold of 1.5) were calculated with an without accounting for the presence of LGE and results compared.All patients had LGE (scarred area 12.5 ± 5.7%). Before considering LGE, average stress MBF, rest MBF and MPR were 2.39 ± 0.94, 0.94 ± 0.42 and 2.83 ± 2.24, respectively. In areas of viable myocardium (LGE-), stress MBF, rest MBF and MPR were 2.82 ± 0.69,1.01 ± 0.26 (p = 0.01) and 3.25 ± 0.58, respectively. In areas of scar (LGE+), stress MBF, rest MBF and MPR were 1.02 ± 0.57,0.99 ± 0.74(p = ns) and 1.04 ± 0.63 (p = 0.001 vs LGE-), respectively. The overall ischaemic burden (at a MPR threshold of 1.5) was 21.3 ± 12.5%. When excluding areas with LGE, the ischaemic burden was 13.4 ± 6.7%(p = 0.001).This study demonstrates the feasbility of combined high-resolution assessment of quantitative perfusion and late enhancement. Areas of scar did not show any hyperhaemic flow during adenosine stress (MPR of approximately 1). When a threshold of 1.5 is used to define the ischaemic burden, these areas would incorrectly be ascribed to areas of inducible ischaemia if correction for the presence of LGE is not used. Combined high-resolution assessment of quantitative perfusion and late enhancement has the potential to provide more accurate assessment of myocardial perfusion status.