Structural myocardial changes accompany myocardial pathologies such as myocardial ischemia, myocarditis, hypertrophy (HCM) and myocardial remodeling. These changes affect T2 relaxation times which can non-invasively be detected by cardiovascular magnetic resonance imaging (CMR). Since the interpretation of T2 weighted images remains a "risky business" due to subjectivity, the purpose of our study was to evaluate direct T2 value quantification by T2 mapping in different types of cardiomyopathies.T2 maps were calculated from images recorded with a gated multislice GRASE sequence . For creation of T2 maps an exponential decay curve was fitted to the intensity progression of each pixel within the images obtained from the multi echo sequence using a dedicated software based on the graphical programming language LabVIEW . T2 value distribution in 3 short axis slices  were evaluated. Mean, median and standard deviation of values were calculated automatically after manual identification of left ventricular myocardium. T2 maps were analysed in patients with low grade (14-50ng/l) high sensitive troponin T (hsTnT) elevation (n=10), myocarditis (n=10), HCM (n=10) and in a young  as well as elderly subjects  without known structural heart disease (control group).GRASE was successfully implemented into clinical routine protocols  and resulted in a mean prolongation of the imaging protocol of only 5 minutes. Due to non gaussian distributed T2 values, median T2 values were analysed Figure . In caseIn summary, T2 mapping could be successfully implemented in our clinical routine protocols. We found that (i) there seems to be an age related increase in T2 values in the absence of known cardiac disease and (ii) our sequence is able to identify regions with highly increased T2 values caused by myocarditis or low grade ischemia without any contrast in conventional T2 SPIR or LGE.none


The impact of regional wall motion abnormality (RWMA) on the accuracy of heart failure with preserved ejection fraction (HFpEF) diagnosis using the E/e′ ratio, which is a non-invasive parameter of left ventricular diastolic performance, is unknown. The purpose of this study was to elucidate the impact of RWMA of the lateral wall (RWMAlat) on the correlation between E/e′ and invasive parameters of left ventricular diastolic performance.τ) were assessed based on the left ventricular pressure study. Correlation coefficients between E/e′ and these invasive parameters were analyzed and compared between cases with RWMAlat and without RWMA.Three hundred and eight consecutive patients undergoing tissue Doppler imaging and catheterization pressure examination were retrospectively analyzed. E/e′ was calculated as the ratio of early diastolic transmitral flow velocity to mitral annular velocity at the lateral wall. Invasive parameters including left ventricular end-diastolic pressure (LVEDP) and isovolumetric relaxation time constant . Sixty-two patients had RWMA; the remaining 246 did not have RWMAlat. We confirmed that the presence of RWMAlat weakens both the correlations between E/e′ and LVEDP (r = 0.574 vs. r = 0.381), and E/e′ and τ (r = 0.729 vs. r = 0.461).LVEDP and Although E/e′ correlates well with parameters of left ventricular diastolic performance assessed by invasive methods, the presence of RWMAlat worsens this correlation. In cases with RWMAlat, careful assessment is required for HFpEF diagnosis because the diagnostic value of the E/e′ ratio could be decreased compared to patients without RWMAlat. The precise understanding of clinical situations of diastolic heart failure has proven difficult because the diagnostic criteria have not been standardized –6. Recenτ), which is a parameter reflecting left ventricular relaxation [The E/e′ ratio, which is obtained by measurement of the early diastolic transmitral flow velocity (E) and the mitral annular velocity at the early diastolic phase on tissue Doppler (e′), was reported to be a good index for estimating the left ventricular filling pressure –15. E/e′laxation –20. Therlaxation , 21–23.However, the specificity of E/e′ measurements, based on assessing a spot on the lateral or septal wall, is influenced by factors that can reduce the strength of the correlation between the results of invasive versus non-invasive techniques , 24. In τ), we performed correlation analysis and compared correlation coefficients in patients with or without RWMAlat.To study the effect of RWMA at the lateral wall (RWMAlat) on correlations between E/e′ values measured at the lateral wall (E/e′lat) and parameters assessed by invasive techniques  below 30 %, abnormal sinus rhythm , waveform abnormalities , severe mitral annular calcification, and decompensated heart failure in the acute phase.A correlation between E/e′lat and invasive parametersp/dt), and peak rate of fall in left ventricular pressure (negative dp/dt) in addition to LVEDP and τ.To confirm the correlation between E/e′lat and invasive parameters for all 308 patients, we applied Pearson’s correlation coefficient testing. Invasive parameters also included systolic aortic pressure (AoSP), diastolic aortic pressure (AoDP), maximum rate of left ventricular pressure rise (positive dImpact of RWMAlat on the correlation between E/e′ and invasive parametersτ), the correlation coefficients between E/e′ and these parameters were compared in patients with RWMAlat and those without RWMA on echocardiographic assessment.To confirm the impact of RWMAlat on the correlation between E/e′lat and invasive parameters  by an experienced investigator. Comprehensive echocardiographic examination consisted of conventional 2-dimensional, Doppler, and color flow imaging, and TDI.The recorded echocardiographic data were evaluated and assessed based on the recommendations of the American Society of Echocardiography .For 2-dimensional measurements, the LVEF was calculated in apical 4-chamber and apical 2-chamber views at end-diastole and at end-systole by modified Simpson’s rule , 26. PapRegional left ventricular function was assessed by a 17-segment model recommended by the American Society of Echocardiography in a parasternal long-axis, 2-chamber, and 4-chamber orientation, and 3 different levels in short-axis orientation . RWMA waIn M-mode recording, septal wall thickness, posterior wall thickness, and left ventricular internal dimensions were measured over several cardiac cycles in the parasternal short-axis acoustic window to optimize medial–lateral beam orientation. These parameters were measured at the level of the mitral valve leaflet tips at the left ventricular minor axis. The measurements were confirmed by the 2-dimensional method. The thickness of the ventricular wall and chamber size were measured as the distance between the leading edge echoes.In pulsed-wave Doppler echocardiography, the left ventricular inflow velocity pattern, which consists of early diastolic velocity (E) and late diastolic velocity (A), was recorded while the sample volume was placed at the tip of anterior and posterior mitral leaflets.In color flow imaging, the severity of valve regurgitation was evaluated based on the recommendations of the American Society of Echocardiography , 28. RegTDI of the mitral annulus velocity was obtained from the apical 4-chamber view, while a 5- to 10-mm sample volume was placed at the lateral mitral annulus. The diastolic phase of the mitral annulus velocity consists of the early diastolic phase (e′) and the late diastolic phase (a′) as the left ventricular inflow velocity pattern in pulsed-wave Doppler echocardiography. Here, e′ was expressed as E/e′ by calculating the ratio of E to e′.p/dt, negative dp/dt, and τ were measured. Positive dp/dt and negative dp/dt were defined as the maximum and minimum differential values calculated from the following formula:τ was derived from the slope of the graph (−1/τ) plotted as a natural logarithm of the pressure scale on the y-axis and time scale on the x-axis, which was described by the following mono-exponential equation [t is the time from negative dp/dt, P0 the mono-exponential amplitude coefficient, Pτ the mono-exponential time constant, and P∞ is the mono-exponential asymptotic equation.For coronary angiography and left ventricular pressure assessment, a suitable catheter was inserted via either the femoral or radial artery. Coronary angiography was performed by a 4Fr coronary catheter, which was selected to fit each patient’s coronary arteries, and lesions were evaluated based on the American Heart Association classification . Left veequation –36:\docuAoDP and AoSP were also measured after pulling out the catheter from the left ventricle to the ascending aorta. LVEDP, AoDP, and AoDP were recorded as average values of measurements over 3 s. All measurements were recorded while the patients were holding their breath in end-expiratory cycle.P < 0.05 was considered statistically significant. All statistical calculations were performed using JMP version 9 .All data are presented as the mean ± standard deviation (SD). Pearson’s correlation coefficient analysis and simple regression were used to assess the associations between invasive or non-invasive measurements. τ), we compared this correlation coefficient in patients with or without RWMAlat. Ninety-two patients were excluded according to exclusion criteria , and three hundred and eight patients were analyzed in the present study. The baseline characteristics for all 308 enrolled patients are shown in Table n = 183) showed no RWMA, and are regarded as controls for the 41 % (n = 125) who had RWMA at either area. Among these patients with RWMA, 50 % (n = 62) had RWMAlat. Table τ were 1.4 ± 24.9 mmHg and 40.1 ± 19.1 ms, respectively.To study the impact of RWMAlat on the correlation between E/e′lat values and parameters assessed by invasive methods , we analyzed the data for all 308 patients , but the other parameters tested  correlated poorly. Moreover, e′ correlated well with τ .To confirm the correlations between E/e′lat and invasive parameters . Thus, it was confirmed that RWMAlat weakens the correlation between E/e′lat and LVEDP or τ of left ventricular diastolic performance parameters. Table To investigate whether RWMAlat affected the good correlation between E/e′lat and LVEDP and τ, established by invasive techniques, correlate well with the E/e′lat, a non-invasive TDI parameter. However, the presence of RWMAlat on echocardiography weakened the correlation.The present study confirmed that left ventricular diastolic performance, LVEDP and Assessing left ventricular diastolic performance is not only very important for the diagnosis of HFpEF, but also in that diastolic dysfunction contributes to heart failure with reduced systolic function. However, since “diastolic performance” is the product of a complex interaction of different factors in the diastolic phase, no unified parameter of diastolic performance can be established. Therefore, the non-invasive assessment of left ventricular diastolic performance is a far from easy task.The European Society of Cardiology and the American College of Cardiology suggested a diagnostic strategy for HFpEF using E/e′ as the non-invasive diagnostic parameter , 22, becτ, which is the time constant of the descending limb of the left ventricular pressure curve, is a standard parameter of left ventricular relaxation; relaxation disorders result in the prolongation of τ. HFpEF patients with active relaxation disorders show prolonged τ, and τ also correlates well with E/e′ [ith E/e′ .τ, and non-invasively measured E/e′ are clearly assessed by different methodologies. Invasive parameters are obtained from the measurement of left ventricular pressure during isovolumetric relaxation or the rapid filling phase, whereas the E/e′ ratio is obtained by measuring the mitral annular velocity during the rapid filling phase. These differences influence the correlation between invasive parameters and the value of E/e′. It has been reported that various clinical features contribute to decreasing the strength of this correlation [τ might be less stable under certain clinical conditions, but this remains controversial [Parameters of left ventricular diastolic performance established invasively, such as LVEDP or relation , 39. Ommrelation  pointed relation . The coroversial , 40–42.τ than when it is measured at the lateral mitral annulus [τ. Our data suggest that the diagnostic value of E/e′lat for HFpEF is lower in patients with RWMAlat than those without. RWMA may, thus, decrease the accuracy of E/e′ for the diagnosis of HFpEF. We emphasize the necessity of using two E/e′ measurement methods  depending on the clinical situation. At least in cases with RWMAlat, our data suggest that E/e′lat has low diagnostic value in the prediction of left ventricular diastolic performance. If the dissociation between lateral and septal value is shown, the value measured at the site without RWMA has higher credibility.RWMA is regarded as one of the most influential factors contributing to the magnitude of E/e′, because of the characteristics of the measurement methods. The present study showed that it is RWMAlat that worsens the correlation between invasive parameters and E/e′lat. We obtained values of E/e′ using a method whereby e′ was measured from the early relaxation velocity of lateral mitral annulus in an apical 4-chamber view. It has been reported that E/e′ measured at the septal mitral annulus correlates better with LVEDP or  annulus . On the  annulus . These iThere are major limitations to this retrospective study. First, fluid-filled pigtail catheters were used in the pressure measurements, even though they are inferior in frequency response characteristics to a pressure-conductance catheter. Using the latter might result in better correlations of invasive parameters with E/e′. The time interval between echocardiographic assessment and invasive measurement is also a major concern. Moreover, the RWMAlat group tended to have lower systolic function, so it cannot be excluded that differences in baseline characteristics contribute to the weaker correlation in patients with RWMAlat.Significant mitral regurgitation has a possibility to impact on the magnitude of E/e′. Though the present study included only one case (0.3 %) with severe mitral regurgitation, this impact on our outcome is thought to be small.The left ventricular filling pressure or average left atrium pressure were not evaluated as invasive parameters of diastolic performance. These parameters might contribute to provide stronger evidence.In conclusion, the E/e′lat ratio obtained by TDI is well correlated with parameters of left ventricular diastolic performance obtained by invasive techniques. However, E/e′lat might not reflect diastolic performance accurately in cases with RWMAlat. A careful assessment of E/e′lat is required in such patients for the prediction of diastolic performance.


The current "gold standard" CMR sequence for assessing myocardial oedema following STEMI is controversial. T2 Short-Tau Inversion Recovery (T2-STIR) is in widespread clinical use but can lack robustness. Steady state free precession oedema imaging (SSFP/ACUT2E) has emerging data to support it as a more reproducible method for oedema assessment. A novel T2 mapping method is also available to determine myocardial oedema. The potential benefit of this method is that the numerical output of the method is largely independent of myocardial motion, instrumental errors . More recently, imaging early after gadolinium contrast administration (EGE) has been suggested as an alternative to detect myocardial oedema following STEMI. The aim of this study was to assess which of the CMR sequences for detecting myocardial oedema following STEMI is most robust.40 patients day 2 following STEMI were prospectively enrolled into the study. All patients had 2 CMR scans on the same day at least 6 hours apart. 3 slices  were repeated using all 4 sequences, with identical FOV, slice thickness and parameters optimised. 1920 images were analysed offline by 2 observers blinded to other sequence analysis results. The images were analysed using semi-automated software, and the myocardial oedema was expressed as a mass (g). Inter-observer, intra-observer and inter-scan agreement was assessed using the Bland Altman method. Variability was calculated as 1-intraclass correlation coefficient (ICC). The difference between sequences was assessed using a 1 way ANOVA. Qualitative analysis of the infarct related artery (IRA) territory with oedema for each sequence was compared against the IRA at the time of angioplasty.The size of myocardial oedema significantly differs among the 4 sequences (p=0.0008). Bland Altman plots for inter-observer, inter-scan and intra-observer agreements were acquired for the 4 sequences. T2-STIR appears the least reproducible of the 4 techniques, with T2 mapping and EGE with the best intra, inter- observer and inter-scan agreement.Inter-observer .Inter-scan .Intra-observer .Variability was lowest for T2 mapping, followed by EGE (Figure On qualitative analysis, the correct IRA was identified in 83% cases by T2-STIR, 98% by T2 map, 88% by ACUT2E and 95% by EGE.The limitations of T2-STIR are well documented. This is the first study that systematically compared all available techniques to determine the most robust sequence for measuring myocardial oedema following STEMI. This study demonstrates that T2 mapping and EGE are robust methods to be used for surrogate endpoints in clinical studies.This work is funded by the NIHR Bristol Cardiovascular Biomedical Research Unit.


Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period.Between 2010–2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state).The study population included a total of 34 women (mean age 29 ± 3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95 ± 11 mL to 115 ± 14 mL and 98 ± 6 mL to 125 ± 5 mL, respectively (p < 0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111 ± 10 g to 163 ± 11 g and 121 ± 5 g to 179 ± 5 g, respectively (p < 0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE.This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state. Cardiovascular disease in pregnancy is the leading cause of maternal morbidity and mortality in North America ,2. In thThe maternal cardiovascular system is subject to a reversible series of structural and functional adaptations during pregnancy. While these changes are normally well tolerated in healthy women, they can present a serious challenge to pregnant women with underlying cardiovascular disease. Driving these normal hemodynamic changes of pregnancy is a fall in systemic vascular resistance (SVR), resulting from peripheral vasodilation and a low-resistance utero-placental circulation -6. Mean Various diagnostic imaging methods have been used to characterize the hemodynamic and structural adaptations of the maternal cardiovascular system during and after pregnancy. These methods range from the invasive dye-dilution technique in 1915 , the CouIn contrast, cardiovascular magnetic resonance (CMR) is highly reproducible and accurate in the determination of cardiac volumes, and is not limited by variations in ventricular geometry, body habitus, or exposure to ionizing radiation ,26. CMR The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of physiologic maternal cardiac remodeling during the peripartum period.This was a prospective cohort study  of healthy volunteers recruited from prenatal obstetric clinics at two tertiary care centres. Eligible subjects were between the ages of 18 and 35 years old at their last normal menstrual period, carrying a healthy singleton pregnancy, and had no previous pregnancy carried beyond 14 weeks gestational age. Exclusion criteria included multiple gestation; any history of cardiac disease or cardiac surgery; any history of thyroid disease, hypertension or diabetes; any significant pregnancy-related complications including gestational diabetes, gestational hypertension, or pre-eclampsia; and/or the presence of pacemakers, surgical clips or other contraindications to CMR. Cardiac imaging by both TTE and CMR was performed in all patients at two time points: initially in the third trimester and then again approximately three months postpartum. Postpartum imaging was performed as a surrogate for the baseline non-pregnant cardiovascular state and used for comparison with third trimester imaging data. The University of Manitoba Human Research Ethics Board approved the study protocol and informed consent was obtained from all patients.Standard TTE  with a multi-frequency transducer and tissue Doppler imaging (TDI) capability was performed in all patients. All TTE scans were performed with women in the left lateral decubitus position to minimize aorto-caval compression and improve patient comfort in the third trimester. The parasternal long axis view was used to obtain cardiac dimensions for the LV, right ventricle (RV), interventricular septum (IVS), posterior wall thickness (PWT), left atrium (LA) and ascending aorta. The apical four chamber and two chamber views were used to obtain LV end systolic volume (LVESV) and LV end diastolic volume (LVEDV) by manually tracing the endocardium. These measurements allowed for calculation of the LV ejection fraction (LVEF) and stroke volume (SV) using the biplane modified Simpson’s method . Left anThe serial CMR scans were performed using a 1.5 Tesla Siemens Scanner . Breath-hold cine imaging was performed using a segmented TrueFISP sequence  with ECG gating to obtain images representative of the entire cardiac cycle in both long and short axis views. A combination of a 32 channel spine matrix and 6 channel body matrix coil was used. All patients were imaged in a half left lateral decubitus position to minimize aorto-caval compression and improve patient comfort in the third trimester. There were no sedative medications or contrast agents used during this study. Chamber measurements were obtained from the three and four chamber long axis views. Measurement of the aortic sinus, sinotubular junction, and ascending aorta were performed in both the three-chamber and coronal views. Endocardial and epicardial contours were drawn manually for the LV and RV, respectively, at end-systole and end-diastole in each data set with the most basal short axis slice identified as the image which contains at least 50% of circumferential myocardium. Papillary muscles and trabeculations were included in LV and RV mass calculation. Two observers (RD and DJ), blinded to the clinical data, analyzed the CMR images offline using CMR analysis suite .All parametric data was reported as mean ± standard deviation (SD). Categorical data was reported as “n” (percentage). Comparison of non-pregnant and third trimester means for each imaging modality was performed using a paired Student’s t-test. Linear regression analyses were performed to assess the correlation between TTE and CMR for CO, stroke volume (SV) and LV mass. Bland-Altman plots of difference versus mean were performed for CO, SV and LV mass with 95% agreement limits of ± 1.96 SD. The Mann–Whitney U test was used to measure the intra and inter-observer variability for LVEDV and LV mass for both imaging modalities. Statistical significance was defined as p < 0.05. SAS version 8.01  was used to perform the analysis.2. The mean gestational age at third trimester imaging was 237 ± 16 days (34 weeks ± 16 days) and mean number of days for postpartum imaging was 107 ± 25 days (16 weeks ± 25 days).The baseline clinical characteristics of the study population (n = 34) are summarized in Table p < 0.05)  settings are summarized in Table 5) Table .Linear regression analysis for SV, CO and LV mass demonstrated good correlation between both TTE and CMR at baseline and in the third trimester as shown in Figure p < 0.05), while RV volume increased from 93 ± 4 mL to 115 ± 4 mL (p < 0.05). There was no change in the RV systolic function as measured by TTE or CMR.The RV end diastolic diameter (RVEDD) increased significantly from the non-pregnant state to the third trimester, as determined by both TTE (32 ± 5 mm to 39 ± 3 mm) and by CMR (33 ± 4 mm to 39 ± 3 mm) . The A wave increase resulted in a decreased E/A ratio in the third trimester from 1.3 ± 0.1 cm/s to 0.7 ± 0.2 cm/s (p < 0.05), consistent with mild diastolic dysfunction. The mitral DT, IVRT, and tissue Doppler parameters (including E/E’) did not change significantly from non-pregnant to third trimester imaging.Diastolic parameters obtained by TTE are outlined in Table The intra- and inter-observer variability of LVEDV and LV mass using both imaging techniques are shown in Table The diagnostic utility of an imaging modality lies in the knowledge of normal parameters for each variable studied. Without a clear understanding of what is considered normal, diagnosis of disease is challenging, if not impossible. While normal standards of maternal cardiac structure and function are well established for TTE, based on studies conducted since the 1960’s ,20,41-47The maternal cardiovascular system undergoes significant physiologic changes in order to support the developing fetus. Previous studies, using TTE in normal pregnancy, have reported that the HR typically increases by 15-20%, SV increases by 20-25%, and CO increases by 30- 50% -11,13,15During pregnancy, total blood volume expansion leads to an increase in ventricular preload and compensatory structural changes in the LV. The increases in LV volume and myocardial mass are physiologic adaptations enabling the maternal heart to support the demands of the developing fetus. Previous studies have reported an increase in LVEDV and LV mass in the third trimester, relative to the non-pregnant state ,12,14. IAlthough RV dilation is an accepted physiologic change in pregnancy, poor visualization of this chamber on TTE and lack of standardized parameters have accounted for the paucity of data examining RV remodeling during pregnancy. Whereas quantitative assessment of the RV using TTE is difficult due to its complex geometry, CMR serves as the gold standard for non-invasive assessment of this chamber due to its higher spatial resolution and low intra- and inter-observer variability . A previet al. demonstrated a 19% increase in RA dimensions in the third trimester by TTE [During pregnancy, there is physiological dilatation of both atria due to an increase in the effective circulating blood volume. Similar to previous studies that demonstrated an increase in LA volumes by approximately 30% in the third trimester ,14,43, or by TTE . Our stuTraditional Doppler techniques have been used to characterize diastolic function in pregnancy. Previous echocardiographic studies have demonstrated a decline in the ratio of passive filling to atrial contraction-related ventricular filling during diastole in pregnant women at term -48. ThisAlthough TTE is limited in its ability to assess aortic root and ascending aorta dimensions, CMR can provide multi-planar reformations of the great vessels allowing for greater visibility and more accurate quantification . A recenThere are several limitations to the current study. First, we used the postpartum period as a surrogate for the pre-pregnancy state. This was done for logistical reasons as predicting when and whom to image pre-conception to allow creation of a study cohort is neither cost-effective nor practical. Second, since we did not image pregnant women during the first and second trimesters, the degree of structural and functional change in earlier pregnancy was not determined. We performed imaging in the third trimester as several studies have shown that many hemodynamic changes will be fully evolved by 28 weeks gestation ,9. FinalThis CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state. Future studies are warranted to evaluate the role of CMR in the assessment of pregnant women with pre-existing cardiac disease and/or peripartum cardiomyopathy.CMR: Cardiovascular magnetic resonance; CO: Cardiac output; BMI: Body mass index; BP: Blood pressure; BSA: Body surface area; DT: Deceleration time; GA: Gestational age; HR: Heart rate; IVS: Interventricular septum; IVRT: Isovolumetric relaxation time; LA: Left atrium; LNMP: Last normal menstrual period; LV: Left ventricle; LVEF: Left ventricular ejection fraction; LVEDD: Left ventricular end diastolic diameter; LVEDV: Left ventricular end diastolic volume; LVESD: Left ventricular end systolic diameter; LVESV: Left ventricular end systolic volume; PASP: Pulmonary artery systolic pressure; PWT: Posterior wall thickness; RA: Right atrium; RV: Right ventricle; RVEDD: Right ventricular end diastolic diameter; RVEDV: Right ventricular end diastolic volume; RV FAC: Right ventricle fractional area change; SV: Stroke volume; SVR: Systemic vascular resistance; TAPSE: Tricuspid annular plane systolic excursion; TDI: Tissue Doppler imaging; TTE: Transthoracic echocardiography.The authors declare that they have no competing interests.RD, JE, SM, SP, and DJ contributed to the design and enrollment of the study participants. RD, SM, SP, MD, KC, PW, and DJ contributed to the post-processing of the echocardiographic and CMR studies. RD, JE, SM, SP, MD, KC, PW, SM, MH, and DJ contributed to the writing of the manuscript. All authors read and approved the final manuscript.


T2-weighted edema imaging identifies the ischemic area at risk during acute myocardial infarction. Myocardial salvage occurs in the area at risk without late gadolinium enhancement (LGE). The degree of myocardial salvage is prognostically important, but its effect on recovery of left ventricular (LV) function is not known. The purpose of this study was to determine if the degree of myocardial salvage predicts recovery of function after an acute ST-elevation myocardial infarction (STEMI).We assessed patients with no known prior CAD post-STEMI. Imaging was performed within 72 hours of the acute event and was then repeated 6-12 weeks post-infarction. The degree of myocardial salvage was obtained by subtracting the percentage LGE from the T2 area at risk. The degree of salvage was compared to the percentage improvement in LVEF by nonparametric Spearman rank correlation coefficient analysis.Twenty-three patients were recruited for the study. One patient refused a second study, 2 had technical difficulties, and 5 had a baseline LV ejection fraction (EF) of ≥50%, leaving a final study population of 15 subjects. The mean age of the sample was 59.3 ± 11.7 years; 86.7% were male and 93.3% were Caucasian. Hypertension, hyperlipidemia, and tobacco use was present in 40.0%, 73.3%, and 46.7%, respectively. The mean BMI was 30.8 ± 4.1, and 9/15 (60%) had a BMI ≥30. The mean LDL was 118.7 ± 33.0, and the mean HgA1c was 6.7 ± 1.8. The baseline mean LVEF was 42.1 ± 6.6%, and increased to 45.1 ± 9.8%, a mean increase of 3.0%. The mean percentage T2 enhancement was 41.2 ± 17.4%, and the mean burden of LGE was 23.5 ± 14.0%, giving a percentage myocardial salvage of 17.7%. The degree of myocardial salvage correlated moderately with an improvement of LVEF from the acute to recovery CMR, with a Spearman correlation coefficient of 0.59 (p= 0.020).The percentage of myocardial salvage moderately predicts recovery of function after an acute STEMI. Future analysis will focus on identifying additional predictors on post-infarction cardiac magnetic resonance imaging.None.


During a followup of 1364 ± 628 days, 5 cardiac deaths and 20 unscheduled cardiovascular hospitalizations were observed. Among LV diastolic function indices, Tau > 48 ms and e′ < 5.8 cm/s were each significantly associated with lower rate of survival free of cardiovascular hospitalization. Even after adjustment for potential confounders , the predictive value of Tau > 48 ms and e′ < 5.8 cm/s remained significant. No predictive value was observed in EDP, E/e′, or LV ejection fraction. In conclusion, LV diastolic dysfunction, particularly impaired LV relaxation assessed by both cardiac catheterization and Doppler echocardiography, is independently associated with increased risk for cardiac death or cardiovascular hospitalization in patients with known or suspected CAD.We hypothesized that left ventricular (LV) diastolic dysfunction assessed by cardiac catheterization may be associated with increased risk for cardiovascular events. To test the hypothesis, we assessed diastolic function by cardiac catheterization (relaxation time constant (Tau) and end-diastolic pressure (EDP)) as well as Doppler echocardiography (early diastolic mitral annular velocity ( Left ventricular (LV) diastolic dysfunction refers to abnormalities in relaxation, filling, and distensibility . EvidencWe studied 222 consecutive Japanese patients who underwent cardiac catheterization for the evaluation of CAD between January 2004 and August 2006. All the patients had symptoms suggestive of angina and/or clinical signs of CAD . No patients with acute coronary syndrome, congestive heart failure, atrial fibrillation, primary valvular diseases, idiopathic dilated or hypertrophic cardiomyopathy, congenital heart disease, end-stage renal disease on maintenance hemodialysis, or malignant neoplasms were included. Medication status and a history of coronary revascularization were determined by review of medical records. Hypertension was defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg measured by indirect arm-cuff sphygmomanometry at rest or use of antihypertensive drugs. Diabetes was defined as a fasting blood glucose level >126 mg/dL or treatment with dietary modification, insulin, or oral hypoglycemic agents. Dyslipidemia was defined as low-density lipoprotein level ≥140 mg/dL, high-density lipoprotein level <40 mg/dL, and/or triglyceride level ≥150 mg/dL or treatment with antihyperlipidemic agents. Within a week before the index cardiac catheterization for this study, blood chemistry was obtained for assessment of clinical features. All the patients gave written informed consents to participate in the study, and this study was performed according to the regulations proposed by the Ethical Guidelines Committee of the Nagoya City University Graduate School of Medical Sciences.Before contrast material was injected into the LV or coronary artery, LV and aortic pressure waves were obtained with a catheter-tipped micromanometer  and recorded on a polygraph system  as previously reported . From thE) and atrial contraction (A) at the mitral orifice were obtained with the use of pulsed Doppler echocardiography in the apical 4-chamber view. Deceleration time was measured as the time from the peak early filling velocity to termination of early filling. The peak early diastolic annular velocity (e′) was measured with the use of pulsed Doppler echocardiography at the septal and lateral mitral annular sites. The values of e′ measured at both sites were averaged. The median values of measurements of 3 consecutive beats were used for statistical analyses. LV mass was calculated from M-mode echocardiographic measurements [The day before the index cardiac catheterization, ultrasound examination was performed with the use of a commercially available echocardiographic machine  with a 3-MHz transducer. Patients were examined at rest in the left lateral decubitus position. LV diastolic function was evaluated according to the published guideline . Transmiurements  and LV mFollowup was determined in October 2010 with the use of the medical record and/or at regular visit to determine the patients' vital status and any cardiovascular hospitalizations. The outcome of the present study was cardiac death  or unscheduled admission for cardiovascular causes. Sudden cardiac death was defined as unexpected death within one hour after the onset of a new symptom, or unexpected, unobserved death.t-test and the Fisher exact probability test. The association between continuous variables was determined by Pearson's correlation analysis. Survival curves of patients stratified by LV function indices were calculated by the Kaplan-Meier method and compared using the log-rank test. EDP of 16 mmHg, Tau of 48 ms, and EF of 50% were used as cut-off points, because these values are established thresholds for separating normal and abnormal levels [e′ and E/e′) for the diagnosis of diastolic dysfunction or the prediction of adverse prognosis are variable depending on age [e′ recorded at lateral mitral annular site is usually higher than e′ at septal site [P < 0.05 was considered significant.We used the SAS program package  for statistical analyses. Differences in quantitative and categorical data at baseline between groups were compared by the Student's g on age  and popue′ and were less likely to have hypertension. Based on the findings of the index coronary angiography, 50 percutaneous coronary interventions and 2 coronary artery bypass surgeries were performed. During a followup of 1364 ± 628  (median (range), 1444 (16–2433)) days, 5 cardiac deaths (4 heart failure and 1 sudden cardiac death) and 20 hospitalizations due to cardiovascular causes , 3 heart failure, and 2 arrhythmia) were observed. Clinical, hemodynamic, and echocardiographic features of all patients and patient subgroups are shown in e′ and E/e′ were determined as 5.8 cm/s  and 13.2 , respectively. Among LV function indices, significant univariate predictors for death or cardiovascular hospitalization included Tau > 48 ms  and e′ < 5.8 cm/s . In contrast, no significant predictive value was observed in EDP > 16 mmHg , EF < 50% , or E/e′ > 13.2 . Survival curves of patients stratified by Tau and e′ are shown in P < 0.01). Based on receiver-operating characteristic analyses for the prediction of death or cardiovascular hospitalization, the best cut-off points for e′ are shown in β-blockers, and to undergo coronary revascularization after the index cardiac catheterization. Compared with patients with e′ ≥ 5.8 cm/s, those with e′ < 5.8 cm/s were more likely to be older, to have diabetes and history of myocardial infarction, to be prescribed angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and to undergo coronary revascularization after the index cardiac catheterization and were less likely to be prescribed calcium blockers.Clinical features of patients stratified by Tau and e′ are also shown in Tables e′ ≥ 5.8 cm/s, those with e′ < 5.8 cm/s were more likely to have greater number of coronary arteries narrowed and higher levels of Tau, EDP, and LV volumes and lower levels of EF. Hemodynamic and echocardiographic features of patients stratified by Tau and e′ < 5.8 cm/s (n = 41)) were more likely to be older, to have history of myocardial infarction, to be higher in serum creatinine levels, LV volume, and LV mass index, and to be lower in EF, compared with those who were diagnosed to have abnormal LV relaxation by only one modality (n = 82).Patients who were diagnosed to have abnormal LV relaxation by both cardiac catheterization and Doppler echocardiography , the predictive value of Tau > 48 ms continued to be significant . Similar5.8 cm/s .e′  and E/e′  and EDP correlated with E/e′  but not with e′ .Modest but significant correlations were observed between LV diastolic function indices determined by cardiac catheterization and those by Doppler echocardiography; Tau correlated with e′ < 5.8 cm/s were each associated with an increased risk for cardiac death or subsequent cardiovascular hospitalization in patients undergoing cardiac catheterization for CAD. In contrast, no prognostic value was observed in EDP, E/e′, or EF.In the present study, we found that Tau > 48 ms and E/e′ ≥ 15 were each predictive of future heart failure events. In contrast, in our study, no prognostic value was observed in EDP or E/e′. Compared with a cohort of Liang et al., our patients had lower EDP (18.2 ± 7.3 versus 14.4 ± 5.4 mmHg) and E/e′ (12.5 ± 5.6 versus 9.6 ± 3.3) levels, due probably to that patients with congestive heart failure were not included in our study. Thus, EDP or E/e′ may not be predictive of adverse prognosis in a cohort of patients without congestive heart failure in which the majority have normal or slightly elevated EDP and E/e′.Although studies have reported that LV diastolic abnormalities assessed by Doppler echocardiography are predictive of cardiac mortality and morbidity in patients with myocardial infarction , those we′ on Doppler echocardiography, e′ quantitates the peak velocity of early diastolic longitudinal motion of the mitral annulus [e′ only provides best-available noninvasive assessment of LV relaxation. Our study is significant in showing for the first time the prognostic value of abnormal LV relaxation determined by cardiac catheterization in patients with known or suspected CAD.The strength of the present study is that LV hemodynamic variables were obtained with the use of a micromanometer catheter but not a fluid-filled catheter. Although a fluid-filled catheter accurately measures late diastolic LV pressures, it cannot precisely determine rapidly changing pressures as occur during LV isovolumetric relaxation . Use of  annulus  and measAlthough the present study does not provide direct mechanisms underlying the association between abnormal LV relaxation and adverse prognosis in patients with known or suspected CAD, there are possible explanations. The most common cause of cardiac death or cardiovascular hospitalization in our study was ischemic myocardial events. It is well-established that the presence of myocardial ischemia impairs LV relaxation . In factAnother possible explanation for our observed association of impaired LV relaxation with adverse prognosis is that LV diastolic abnormalities may coexist with other disorders that may adversely impact on prognosis. Specifically, Lee et al. reported that altered LV diastolic function assessed by Doppler echocardiography was independently associated with endothelial dysfunction and hemostatic abnormalities , both ofE/e′. Forth, our study patients were composed of stable known or suspected CAD patients without congestive heart failure who were referred for cardiac catheterization for assessment of CAD. Our findings cannot be extended to other populations. Finally, our study is not large enough to permit us to evaluate the association of LV diastolic dysfunction with specific causes of death or hospitalization.There are several limitations in the present study. First, LV mass was available in the limited number of the patients (68%), which could have influenced our results . Furthere′ by Doppler echocardiography may provide useful information for risk stratification in known or suspected CAD patients without congestive heart failure. The cut-off point of e′ used in the present study, however, is higher than that previously reported. Specifically, Wang et al. reported that e′ < 3 cm/s was a powerful predictor for cardiac death in patients with reduced (<50%) EF [e′ < 3.5 cm/s for cardiac death in hypertensive subjects with LV hypertrophy [e′ for the prediction of adverse prognosis may be variable depending on population studied. Further studies are necessary for determining the optimal cut-off points of e′ for identifying high-risk patients in various populations.Our study suggests that measurement of <50%) EF . Similarertrophy . These rOur findings suggest that patients with impaired LV relaxation may need more aggressive treatment of CAD. A recent study has reported that altered LV relaxation assessed by Doppler echocardiography is improved after coronary revascularization in patients with ischemic cardiomyopathy . The pro


This study aimed at analyzing the feasibility of T1 and T2 mapping at 3 T and providing reference values.Myocardial T1 and T2 mapping in 3 short-axis slices at 3 T. For T2 mapping, 3 single-shot steady-state free precession (SSFP) images with different T2 preparation times were acquired. For T1 mapping, modified Look-Locker inversion recovery technique with 11 single shot SSFP images was used before and after injection of gadolinium contrast. T1 and T2 relaxation times were quantified for each slice and each myocardial segment.Sixty healthy volunteers  underwent left-ventricular T2 and T1 (pre-/post-contrast) times were: 44.1 ms/1157.1 ms/427.3 ms (base), 45.1 ms/1158.7 ms/411.2 ms (middle), 46.9 ms/1180.6 ms/399.7 ms (apex). T2 and pre-contrast T1 increased from base to apex, post-contrast T1 decreased. Relevant inter-subject variability was apparent (scatter factor 1.08/1.05/1.11 for T2/pre-contrast T1/post-contrast T1). T2 and post-contrast T1 were influenced by heart rate , pre-contrast T1 by age (p < 0.0001). Inter- and intra-observer agreement of T2  and T1  were high. T2 maps: 97.7% of all segments were diagnostic and 2.3% were excluded (susceptibility artifact). T1 maps (pre-/post-contrast): 91.6%/93.9% were diagnostic, 8.4%/6.1% were excluded (predominantly susceptibility artifact 7.7%/3.2%).Mean T2 and T1 reference values for the specific CMR setting are provided. The diagnostic impact of the high inter-subject variability of T2 and T1 relaxation times requires further investigation.Myocardial T For all these reasons this study scrutinizes myocardial T1 and T2 at 3 T in a large sample of healthy volunteers using state-of-the art mapping techniques.Cardiovascular magnetic resonance (CMR) provides techniques for non-invasive myocardial tissue characterization. Tormation . Most oformation . Many of60 healthy volunteers were enrolled into the study . The st0-shimming based on field maps derived from double-gradient-echo acquisitions was performed to improve static field uniformity. The following CMR protocols were used  using a 32-channel cardiac RF coil for signal reception, the integrated body RF coil for transmission, and ECG for cardiac gating. Subject-specific, volume-selective first- and second-order Bd Figure .2, matrix 156 × 192, slice thickness 6 mm, receiver bandwidth (BW) 704Hz/px, parallel imaging using GRAPPA reconstruction (R = 2), 30 cardiac phases.Steady-state free-precession (SSFP) cine images were obtained during repeated breath-holds in three long axes  and in a stack of short axes (SAX) covering the left ventricle (LV) to assess wall motion and for cardiac chamber quantification. Imaging parameters were: repetition time (TR) 3.1 ms, echo time (TE) 1.3 ms, asymmetric echo with factor 0.29, flip angle (FA) 45°, field of view (FOV) (276 × 340)mm2 mapping, data were acquired in basal, mid-ventricular, and apical SAX planes using a T2-prepared single-shot SSFP technique similar to the one described for 1.5 T [2 preparation pulses were employed to improve the homogeneity of the T2 weighting. Three SSFP images, each with different T2 preparation time  were acquired in end-diastole within one breath-hold. Imaging parameters were: TR = 2.4 ms, TE = 1 ms, FA = 70°, FOV = (340 × 278) mm2, matrix = 176 × 144, slice thickness = 6 mm, BW = 1093Hz/px, GRAPPA acceleration factor 2, linear phase encoding scheme. To correct for residual cardiac and respiratory motion between image sets, a non-rigid registration algorithm was used [2-map was generated using unsupervised curve-fitting based on a two-parameter equation [T2P was chosen to balance accuracy and acquisition time (7 heart cycles) [For T 340 × 27 mm2, mat1 mapping, data were acquired in basal, mid-ventricular, and apical SAX planes before and 10 minutes after administration of 0.2 mmol/kg i.v. gadobutrol . Data were obtained in end-diastole using a cardiac-gated, SSFP-based Modified Look-Locker Inversion Recovery (MOLLI) technique [2, matrix = 156 × 208 to 168 × 224, slice thickness = 6 mm, BW = 1045-1028Hz/px, GRAPPA acceleration factor 2, linear phase-encoding ordering, minimum TI of 91 ms. To generate a pixel-wise myocardial T1-map, single-shot SSFP images were acquired at different inversion times  was repeatedly adjusted to appropriately null the myocardium during the length of LGE image acquisition. Imaging parameters were: TR = 10.5 ms, TE = 5.4 ms, FA = 30°, FOV (350 × 262) mm42 .Image analysis was done using CMRSSFP cine images were visually evaluated regarding wall motion abnormalities. LV enddiastolic and endsystolic volume and LV mass were determined by manually contouring the endocardial and epicardial borders of the SAX in systole and diastole.The absence of LGE was determined qualitatively by visual assessment.Each single original image was assessed regarding artifacts caused by susceptibility effects, cardiac or respiratory motion. Each motion-corrected series was evaluated whether the images were correctly aligned. Each map was evaluated whether the original images were transformed to a reasonably appearing map. The presence of artifacts led to the exclusion of all affected myocardial segments. Two experienced readers assessed quality in consensus.The LV myocardium was delineated by manually contouring the endocardial and epicardial border. We ensured that the region of interest (ROI) was definitely within the myocardium and did not include blood or epicardial fat based. An endocardial and epicardial contour was drawn in one original motion-corrected image. The trabeculated layer and the epicardial border were left out. In doubt, SSFP cine images were consulted. The contours were copied to the other images and adapted to fit in all of these. These final contours were copied to the map. The myocardial ROI was automatically segmented according to the AHA segment model . Results1 values were recorded from pre-contrast and post-contrast T1 maps applying the same procedure as for T2.T2 and pre-contrast T1 values of each LV segment twice with at least 3 months of time between the measurements. A second observer measured T2 and pre-contrast T1 values blinded to the other results.Intra- and interobserver variability were tested in a subgroup of 20 randomly selected subjects , where one observer measured T1 and T2, the scatter factor was provided as back transformed SD, which allows a similar interpretation as the coefficient of variation for non-transformed data. All values presented were back transformed using the exponential to present the data on the original scale. Spearman's correlation coefficients were calculated to evaluate correlations between the co-factors, which may interfere with the modelling. A p-value of less than 0.05 was regarded as statistically significant. Calculations were performed using SAS 9.2 . Intra- and inter-observer dependency was assessed by Bland-Altman analysis and Pearson’s correlation using Prism 5.0 .Baseline characteristics are shown as means with standard deviation (SD) or absolute frequencies. Relaxation times are displayed as least-square means with 95% tolerance intervals (90% coverage) and were assessed by slice and by segment using mixed linear models on logarithmic transformed data to ensure normal distributed data. The following co-factors were included into each model to assess their impact on the relaxation times: age (categories), gender, heart rate (binary with split at median), blood pressure and excluded backwards if not significant. For T2 maps were available for 58 subjects, pre-contrast T1 maps for 59 subjects and post-contrast T1 maps for 57 subjects.All 60 CMR scans were performed without major adverse events. The scans were incomplete in 4 subjects. TFrom 922 segments, 901 (97.7%) were eligible for analysis Figure  mainly i2 relaxation times per slice are shown in Table T2 values for each myocardial segment are presented in Figure 2 results is illustrated in Figure T-1) was found to significantly influence T2 measurements (p < 0.0001). A heart rate higher than the median (69.5 min-1) was associated with lower T2 values . Other tested cofactors including age and gender were not found to be significant.Heart rate (ranging from 47 to 102 min1 mapping 938 segments were obtained. 859 (91.6%) were eligible for analysis .T1 values for each myocardial segment are shown in Figure 1 of the anterior segment was lower than in the other segments. The distribution of all individual T1 results is illustrated in Figure T1 relaxation times (p < 0.0001). The difference was small between age category 20–39 years and 40–59 years. A clear decrease of T1 relaxation times was observed for subjects ≥ 60 years  were eligible for analysis  with higher heart rates than the median (69.5 bpm) being associated with lower post-contrast T1 relaxation times . Other tested cofactors including age and gender were not found to be significant.Heart rate was found to significantly influence the post-contrast T2 and pre-contrast T1 mapping inter- and intra-observer analysis demonstrated close agreement  T2 and T1 mapping achieve a high grade of diagnostic image quality, although susceptibility artifacts entailed the exclusion of a limited number of myocardial segments from the analysis. ii) Observer dependency of T2 and T1 relaxation time quantification was low. iii) Mean values and 95% tolerance interval of myocardial T2 and T1 relaxation times are presented per slice and per segment and can be used as reference values specific for this MR setting.iii) An inter-subject distribution of T2 and T1 values became apparent and may constitute a limitation to define appropriate cut-offs.This study examined myocardial T2 mapping at 1.5T did not report the exclusion of segments from analysis due to SSFP off-resonance or banding artifacts [0 inhomogeneity across the heart. The use of an appropriately selected delta frequency may be an option to resolve some artifacts and deserves further systematic investigation. The artifacts mainly affected the inferolateral region, where pathologies like myocarditis may also exhibit their predominant lesion [Previous studies with SSFP-based Trtifacts . Hence, t lesion . Despite2 relaxation times derived from T2-prepared SSFP imaging in this study are higher compared to a black-blood multi-echo spin-echo approach at 3 T, which provided a mean value of T2 = 39.6m sin the septum [2 reported here was found to be lower versus a mean T2 = 52.2 ms reported for T2 prepared SSFP imaging at 1.5 T [2 values, and iii) T1 relaxation effects due to higher T1 values at 3 T versus 1.5 T. Generally, myocardial T2 reported in the literature varies substantially, ranging from about 50 ms to 58 ms at 1.5 T [2 relaxation time is very sensitive to cofactors and emphasizes the need to generate reference values specific for each technique and imaging setting.Te septum . Myocard2 increased from base to apex, which is in accordance with a recent work using a similar mapping technique at 1.5 T [Our results showed that Tat 1.5 T . The mosat 1.5 T . We trie2 values averaged over all myocardial segments or only for a midventricular slice. By averaging T2 values over the whole slice or the whole heart, focal T2 deviations may be overlooked. The present study is the largest study, which reports T2 values for each myocardial segment and slice.Most of the previous studies reported T2 values, the segmental T2 values increased from base to apex. In comparison, Markl et al. reported T2 values from 50.5 ms to 51.6 ms in the basal slice and 54.3 ms to 56.1 ms in the apical slice at 1.5 T [As reported for the global Tat 1.5 T .2 values was relatively large both per-slice and per-segment. This finding is in concordance with Thavendiranathan et al., who described T2 values ranging from about 50 ms to 62 ms in healthy controls [2 mapping, given that the difference in T2 between healthy and injured myocardium has been reported to be relatively small, e.g. 13 ms/11 ms between infarct core/myocarditis and remote myocardium [The inter-subject variability of absolute Tcontrols , and witocardium .2 relaxation time is under discussion. Giri et al. reported that the variability between healthy subjects was unrelated to heart rate. Other studies reported lower T2 values in patients with higher heart rate [1 relaxation effects caused by incomplete T1 relaxation, which may affect T2 mapping using a SSFP-based approach. This finding is very relevant for clinical practice as subtle T2 increases may disappear in acutely ill patients with higher heart rates.The association of heart rate and Tart rate ,4. This 1 mapping demonstrated diagnostic image quality for the vast majority of myocardial segments. However, a relevant number of myocardial segments had to be excluded due to technical challenges, which would lead to diagnostic uncertainty in a clinical scenario. Previous studies at 1.5 T and 3 T reported lower rates of artifact-related non-diagnostic segments [Tsegments ,10,16,171 values are in concordance with Piechnik et al., who reported T1 = 1169 ms averaged over all myocardial segments [1 values (T1 = 1315 ms or T1 = 1286 ms) were reported when using a T1 mapping technique similar to that used in this study [1 relaxation times are sensitive to many influencing factors.The pre-contrast Tis study ,18. Thes1 relaxation times reported here can be regarded as reference values specific only for this cohort, time point, mapping technique, type and dosage of contrast media. Further comparisons with other published results are difficult unless an identical study design is used. To provide a context, Lee et al. used 0.15 mmol Gadolinium DTPA and measured a mean T1 of about 550 ms in one midventricular slice after 8.5 min in healthy human subjects at 3 T [The myocardial Ts at 3 T .1 times increased from base to apex, whereas the post-contrast T1 values decreased from base to apex. Partial-volume effects owing to the curvature of the left ventricle can most probably explain this finding with blood signal being included into the voxel. While some completely exclude apical T1 maps from analysis [We observed that the pre-contrast Tanalysis , we trie1 values of the anterior segments were lower than T1 observed for the other segments. Interestingly, Piechnik et al. observed the identical pattern with MOLLI at 3 T [1 values inspite of using a different classification into “septal” and “non-septal” myocardium [In agreement with Kawel et al. we did not observe significant segment-to-segment differences post-contrast . HoweverI at 3 T . Kawel eocardium . Althoug1 values was notable both per-slice and per-segment, including extreme outliers. This finding is in concordance with other T1 mapping studies reporting pre-contrast T1 values at 1.5 T ranging from 862 ms to 1105 ms in healthy volunteers [1 mapping, given that the difference in T1 times between healthy and injured myocardium has been reported to be relatively small depending on the underlying disease. Dall’Armellina et al. reported a mean pre-contrast T1 value of 1257 ± 97 ms for acutely infarcted segments compared to 1196 ± 56 ms for normal unaffected segments at 3 T [1 may already be accurate enough to differentiate cardiac amyloid patients from normals [The inter-subject variability of absolute Tlunteers  and a colunteers . The higs at 3 T . In othe normals .1 in the present study was even more variable between subjects than pre-contrast T1, attributable to the many factors with influence on the contrast kinetics . Miller et al. recently demonstrated that even though isolated post-contrast T1 measurement showed significant within-subject correlation with histological collagen volume fraction, the between-subject correlations were not significant. Hence, isolated post-contrast T1 measurement seems to be insufficient for assessing extracellular volume fraction [Post-contrast Tfraction .1 values. This is an interesting aspect that may reflect early age-dependent alterations of myocardial texture. Dall’Armellina et al. and Ugander et al. showed that pre-contrast T1 times were increased in acute myocardial ischemia [1 in cardiomyopathies. Hence, the present reduction of pre-contrast T1 with age may sound contradictory [1 values [1 mapping in non-ischemic heart disease in future.Aging was found to be associated with decreasing pre-contrast Tischemia ,23. Dassadictory . In cont1 values . Therefo2 and T1 mapping at 3 T are feasible with a good diagnostic image quality, although susceptibility artifacts related to the magnetic field strength of 3 T triggered exclusion of myocardial segments from analysis. This study provides reference values for myocardial T2 and T1 relaxation times per slice and per segment for the specific MR setting, which were deduced from a large cohort of healthy volunteers. With this approach a relatively high inter-subject distribution became apparent, which may constitute a relevant challenge for the definition of cut-offs that differentiate healthy from diseased myocardium in clinical practice.In conclusion, myocardial T2 and T1 relaxation times could not be assessed. ii) Whereas observer variability to assess T2 and T1 relaxation times was low, the inter-scan variability was not assessed and deserves further investigation. iii) Regarding T1 estimation by the applied MOLLI technique, there are known limitations to inversion efficiency [2. At the time the study was designed, an improved inversion pulse designed for myocardial T1 mapping tailored for myocardial T2 was not available yet. The limitations of evaluating T1 based on magnitude images are described in a recent publication [i) As hematocrit was not measured in this study, its effect on Tficiency  and to elication . By the The co-author A. Greiser is employee of Siemens Healthcare, Germany. The other authors declare that they have no competing interests.FvKB defined the design of the study, headed its coordination, acquired the image data, read the images, assisted in statistical analysis and drafted the manuscript. MP contributed to the analysis and interpretation of the data and was involved in drafting the manuscript. MD made contributions to acquisition of data and was involved in drafting the manuscript. RW and AG made substantial contributions to the analysis and interpretation of the data and were involved in drafting the manuscript. CS participated in the design of the study, performed the statistical analysis and was involved in drafting the manuscript. TN made substantial contributions to the acquisition, analysis and interpretation of the data and was involved in drafting the manuscript. JSM defined the design of the study, headed its coordination, assisted in statistical analysis and interpretation of the data, and drafted the manuscript. All authors read and approved the final manuscript.T2-mapping. A full set of T2-weighted SSFP single shot images with 3 different T2 preparation times and the corresponding T2 maps from the basal, midventricular and apical slice. Click here for fileT1-mapping. A full set of T1-weighted SSFP single-shot images and the corresponding pre-contrast T1 maps from the basal, midventricular and apical slice. Click here for file


Hearts, saphenous veins, internal-mammary-arteries and aortas of male landrace pigs were harvested and exposed to cold ischemia in either saline or Custodiol-HTK solution. Mitochondrial function was measured in situ in permeabilized fibers by high-resolution respirometry. Mitochondrial respiratory capacities  were similar in the right and left ventricle in controls and after 14 h of cold storage were significantly better preserved in Custodiol-HTK than in saline solution. Mitochondrial respiration rates in various blood vessels including aorta, arteries and veins were less than 5% of myocardium rates. In contrast to the pig heart, in some blood vessels, like veins, mitochondrial function remained stable even after 24 h of cold ischemia. HTK-Custodiol protection of mitochondrial function after prolonged cold ischemia was observed in the myocardium but not in blood vessels. HTK-Custodiol solution thus offers significant protection of myocardial mitochondria against cold ischemic injury and can be used as efficient preservation solution in organ transplantation but probably has no benefit for blood vessels preservation. Analysis of mitochondrial function can be used as a valuable approach for the assessment of cold ischemic injury in various tissues including pig heart and various blood vessels.The effects of cold storage using Custodiol Preservation solutions may include impermeants and osmotic agents to reduce edema and minimise cellular swelling , buffering capacity against acidosis , energy substrates  to support energy status and antioxidants and inhibitors of ROS production [Analysis of mitochondrial function has become central to basic research of mitochondrial physiology and the diagnosis of many diseases ,2. Assesoduction –21.In the case of coronary artery bypass surgery, graft vessels are harvested from the leg and forearm and stored during surgery until they are used for grafting. Therefore, these blood vessels are exposed to an ischemic period. In most cardiac surgical centers these blood vessels are stored in pure saline solutions, in some instances heparin is added .®) on mitochondrial function was investigated and compared with simple saline solution. Additionally, mitochondrial function in various blood vessels including the ascending aorta, the left internal thoracic artery and the saphenous vein were investigated with regard to exposure to prolonged cold ischemia with and without using preservation solution. Here therefore we show significant benefit of Custodiol-HTK solution in myocardial preservation as compared with saline.In the current study we aimed to assess mitochondrial oxidative phosphorylation as an indicator of mitochondrial function and effects of cold ischemia. Mitochondrial function was measured in the left and right ventricles after 14 h of cold ischemia. In addition, the protective effect of cardioplegic/preservation solution , and complex II (with succinate). This can be important information since the usual strong requirements to use always very standardized biopsy samples regarding ventricle types may probably be avoided. Also, in controls (without cold ischemia), respiration data were not distinguished between the two solutions. Like previous findings using various heart cold ischemia models , 14 h of2.2.Overall, all vessel samples including aorta, arteries and veins showed 20–30 fold lower mitochondrial activity compared with myocardial samples  on cold ischemia-reperfusion injury with respect to mitochondrial respiration through different segments of the electron transport system. Mitochondrial damage during ischemia including cold ischemia is the key event leading to cell death on a cellular level and organ dysfunction on a larger scale ,21–24. Ochondria , we demoRight and left ventricular myocardium showed no difference at mitochondrial level at baseline and the mitochondrial function similarly declined by the same amount in both ventricles when exposed to prolonged cold ischemia. In the clinical setting of heart transplantation it is often the case that the right ventricle recovers slower from ischemia than the left ventricle. Weaning from cardiopulmonary bypass may be difficult due to right ventricular failure. However, this phenomenon can obviously not be explained by the effects of ischemia on the energy metabolism, since mitochondrial function of right and left ventricular myocardium did not differ in our study. An alternative explanation might be the different geometry of the right ventricle and the fact that the right ventricular wall in general is thinner than the left ventricular wall and therefore more vulnerable to stunning. Furthermore, pulmonary hypertension in heart-transplant recipients may significantly impair the right ventricle of the donor heart, which is not adapted to such high pressure-levels. This study thereby contributes to the existing but incongruent knowledge of the superiority of preservation solution over purely saline solutions . Also, ivs.Blood vessels in general have much lower mitochondrial capacities compared with myocardium  influence on mitochondrial respiratory function. Significant advantages of this approach however, as mentioned above, is that many samples can be collected simultaneously and measured later during several days. Also, due to technical problems, we did not analyze cardiac function and effects of reperfusion after cold ischemia and heart transplantation. We now provide metabolic evidence that the short intraoperative ischemic periods (10–24 h) probably have no effect on mitochondrial function in blood vessels. Therefore, in contrast to the heart and some other high-energy metabolism-dependent organs, special storage solutions for blood vessels are of questionable benefit in this application.3.3.1.Male landrace pigs weighing between 60 and 80 kg served as study animals. All animals received human care in compliance with the “Principles of Laboratory Animal Care”  as well as with the Austrian law. The animals were premedicated with intramuscular ketamine (10 mg/kg), intubated, and ventilated at 10 mL/kg with isoflurane (1%–3%) and oxygen. During surgery anaesthesia was maintained with propofol 1%  and piritriamid 75 mg/kg/h .The heart, the ascending aorta, internal mammary arteries and saphenous veins were harvested and immediately prepared for analyses or exposed to cold ischemia at 4 °C in either saline or Custodiol (HTK) solution. Myocardial samples were stored for 14 h. Respirometry of blood vessels was performed at two time points, immediately after harvesting and after 24 h of cold storage.3.2.in situ method for mitochondrial respirometry of cryopreserved and permeabilized muscle tissues as described previously [N,N,N′,N′-tetraacetic acid (EGTA), 1 g/L bovine serum albumin (BSA) essentially fatty acid free, 3 mM MgCl2, 20 mM taurine, 10 mM KH2PO4, 20 mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), pH 7.1. DatLab software  was used for data acquisition and analysis. Respiration was stimulated by 1 mM adenosine diphosphate (ADP)  and measured with 10 mM glutamate and 5 mM malate  or using 10 mM succinate and 0.5 μM rotenone (substrate for complex II). Typically, the stimulatory effects of ADP (state3/state2 ratios) in cryopreserved myocardial preparations were in range 3.4–4.7 in the presence of complex I substrates glutamate + malate.We used an eviously . Myocardeviously ,9 and creviously . Since oeviously . Mitochoeviously ,21) and 3.3.® Dr. Koehler Chemie GMBH, Alsbach-Haenlein, Germany) solutions were used for organ flush and cold storage. EGTA, BSA, HEPES and ADP were purchased from “Sigma” .Filtered  saline and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK; Custodiol4.In summary, HTK-Custodiol solution offers significant protection of myocardial mitochondria against cold ischemic injury and can be used as efficient preservation solution in organ transplantation. High-resolution respirometry analysis of mitochondrial function in permeabilized preparations can be used as a suitable method for the assessment of cold ischemic injury in various tissues including heart and also various blood vessels.


B-type natriuretic peptide (BNP) is a member of a four-natriuretic peptide family that shares a common 17-peptide ring structure. The N-terminal fragment (NT-pro-BNP) is biologically inert, but both are secreted in the plasma in equimolar quantities and both have been evaluated for use in the management of congestive heart failure. BNP and NT-pro-BNP are frequently used in the diagnosis of congestive heart failure and distinguishing between patients with dyspnoea of cardiac or pulmonary origin. Values of NT-pro-BNP are affected by age or the presence of one or several co-morbidities such as chronic renal failure, type 2 diabetes, and acute coronary syndrome. ‘Normal’ values of these peptides also vary depending on the type of test used. The performance characteristics of these tests vary depending on the patients on whom they are used and the manufacturer. For this reason, the determination of reference values for this peptide represents such a challenge. BNP was initially discovered in the porcine brain, but the largest concentrations are found in the heart. It is a peptide with 32 amino acids, synthesised in the ventricles as a response to stretching of the myocytes and/or pressure overload. It is released as an active hormone and as an inactive N-terminal fragment (NT-pro-BNP).1Once released in the blood flow, BNP has numerous physiological actions, their net effect being to reduce pre- and post-load. Specifically, BNP produces a decreased vascular tonus by relaxing the smooth muscles, leading to a decrease in post-load. In addition, it induces a movement of fluid into the interstitial space, thus leading to a decrease in pre-load.BNP reduces the proliferation of fibroblasts and smooth muscle cells, sympathetic nervous activity, water and salt retention, release of the antidiuresis hormone, and synthesis of aldosterone and its release from the adrenal glands. In the kidneys, BNP increases glomerular filtration rate and renal blood flow by increasing the outgoing arterial tonus and decreasing the ingoing one. In addition it decreases the release of renin and the reabsorption of sodium, leading to diuresis and natriuresis.2The N-terminal fragment of BNP is derived from proteolysis of pro-BNP, which is composed of 108 amino acids. It consists of 76 amino acids and has recently caused great interest, due to its possible role in monitoring heart failure and distinguishing acute coronary syndromes. Its effects on diuresis and natriuresis in patients with congestive heart failure represent a compensatory mechanism for stress on the myocytes, which leads to ventricular dysfunction.1Serum levels of natriuretic peptides are important, not just as indicators of numerous cardiovascular deficiencies but also as markers of their severity.1 For patients with acute coronary syndromes, the determination of BNP levels offers predictive information on the apportioning of risk, in the absence of elevation in the S-T interval. In addition, BNP and NT-pro-BNP have prognostic significance for acute pulmonary embolism.1et al.4The diagnostic value was recently confirmed by Coutance With regard to the prognostic value of NT-pro-BNP for chronic heart failure, the Val-HeFT study  demonstrated the positive nature of advanced heart failure. Moreover, BNP concentrations appeared significantly increased in patients with dilated cardiomyopathy and cardiovascular disease in NYHA classes III or IV, but it could not predict mortality or the requirement for a heart transplant.4Despite the evidence that BNP is secreted in ventricular overload states, there is an individual and inter-individual variation in both healthy subjects and those with stable chronic heart failure, which makes the interpretation of BNP levels difficult. Multiple studies have shown that only changes in BNP level larger than approximately 113 to 130% and changes in NT-pro-BNP larger than 90 to 98% can be considered to have exceeded individual, inter-individual and analytical variations.2There are several reasons for these variations. In healthy subjects, BNP level is connected to gender and age; its levels increase with age and are higher in women than in men. Despite increases with age, BNP and NT-pro-BNP proved effective in excluding congestive heart failure in an elderly population that presented with acute dyspnoea. Race also plays a role, with a higher variability being seen in African-Americans than Caucasians.7Levels of BNP are lower for obese patients compared to non-obese. In addition, it was observed that genetics plays a role in the variability of BNP levels. Along with age, gender, genetics and body mass index, there are other physiological reasons for the variability of BNP.Renal function also affects levels of BNP, significantly increased levels being recorded for those with renal dysfunction. Patients on haemodialysis showed significant rhythmic oscillations in BNP levels, compared to healthy subjects.2The lack of a single set of normal values due to different idiopathic levels and the available commercial kits can lead to confusion in clinical application. While some researchers claim that values above 100 pg/ml indicate heart failure, others suggest a value above 200 pg/ml. The ADHERE study, which included over 48 000 patients, indicated as prognosticators of mortality values over 430 pg/ml.9Chronic heart failure is an illness that is appearing with increasing frequency, especially in elderly patients. Nevertheless, classification is often difficult due to non-specific symptoms and the lack of a ‘gold standard’ protocol for a correct diagnosis.9Measurement of plasma concentrations of BNP has proved to be a very efficient screening technique for the identification of patients with various heart diseases, regardless of aetiology and the degree of systolic dysfunction of the left ventricle, which has the potential to develop into manifested heart failure and has a high risk of producing a cardiovascular event. Recently, the Food and Drug Administration approved NT-pro-BNP for evaluation of the prognosis of patients with congestive heart failure and acute coronary syndromes. Determination of BNP level was also approved for risk segregation in acute coronary syndromes.10Multiple studies have confirmed the efficiency of the determination of BNP concentrations in the plasma of patients with acute dyspnoea. The Breathing Not Properly study is an example, in which 1 586 patients participated.2Together with its role in acute decompensated heart failure, levels of BNP are also high for diastolic dysfunction. Increased BNP levels can be found with isolated diastolic dysfunction, hypertrophic cardiomyopathy, or associated with systolic dysfunction. Echocardiographic parameters correlated with BNP levels include mass index of the left ventricle, its end-diastolic volume and isometric relaxation time. The further the stage of diastolic dysfunction the higher the levels of BNP.2As with congestive heart failure, BNP level has a prognostic value for acute coronary syndromes. BNP is additive with, and independent of, the increases in troponin I for these syndromes.2A sub-study of Breathing Not Properly showed that plasma levels of BNP were high for patients with atrial fibrillation that was not diagnosed with congestive heart failure, but its levels were not different in the presence of heart failure.2For patients with mitral insufficiency, an increased BNP level was correlated with mortality and the onset of congestive heart failure, regardless of the degree of regurgitation present on echocardiography, suggesting that BNP is a reflection of its atrial and ventricular consequences.2In unstable angina, NT-pro-BNP represents an effective marker of the damage produced by cardiac ischaemia. The severity of the coronary disease is shown by an increase in the levels of NT-pro-BNP. In addition, in the case of acute coronary syndromes, NT-pro-BNP had an immuno-modulating role and offered important information for the prognosis of patients.1et al.p < 0.001).14Castro p < 0.001), peak CK-MB  and low left ventricular ejection fraction ; no correlation was found with the TIMI risk score . Multivariate analysis revealed that left ventricular ejection fraction and troponin I levels were independently correlated with NT-pro-BNP levels .14Increased levels of NT-pro-BNP were associated with increases in troponin I  were measured. All patients were also part of the PRIME-II study that investigated the effects of ibopamine on the causes of mortality in patients with moderate or severe heart failure.19Most of the neurohormones were similar between the two groups, but patients with diabetes had higher values of BNP and NT-pro-BNP. The patients were monitored for five years, and during this time, 195 died, of whom 51 had diabetes. For patients with diabetes, noradrenaline, ANP, NT-pro-ANP, BNP and NT-pro-BNP levels were significantly higher than in those who did not survive. Therefore BNP and NT-pro-BNP proved the strongest predictors of outcome for both groups of patients.19The most likely explanation for the increase in BNP and NT-pro-BNP levels in these patients with diabetes was the presence of diastolic dysfunction.20Cirrhotic cardiomyopathy is an under-diagnosed condition. This is most likely due to the fact that there is no single diagnostic test to identify these patients.21et al.23Numerous recent studies demonstrated that patients with hepatic cirrhosis had increased plasma concentrations of BNP and NT-pro-BNP, representing markers of early ventricular dysfunction. Henriksen A study conducted on 153 patients subjected to a liver transplant determined their BNP levels post-transplant and on days 1 and 7. It was observed that a BNP level higher than 391 pg/ml immediately after the liver transplant appeared to be an early marker for heart dysfunction related to the cirrhosis.24In patients with dyspnoea, overlapping or even conflicting history, physical and radiographic findings often hinder the differentiation between cardiac and non-cardiac aetiology. The primary value of BNP and NT-pro-BNP testing in the emergency department is its diagnostic value in the differential diagnosis of acute dyspnoea and possible congestive heart failure.Levels of natriuretic peptides may also assist the emergency physician in appropriately triaging the patient with congestive heart failure.25After multiple studies, the conclusion was reached that levels of BNP < 100 pg/ml and > 500 pg/ml have a positive and negative predictive value, respectively, of 90% for the diagnosis of congestive heart failure for patients presenting with acute dyspnoea. For values between 100 and 500 pg/ml, the physicians must consider underlying left ventricular dysfunction, the effects of renal failure, or right ventricular dysfunction secondary to chronic pulmonary disease or acute pulmonary embolism.25The recommended thresholds of less than 100 pg/ml to rule out heart failure and more than 500 pg/ml to rule in heart failure have been estimated to have the following likelihood ratios (LRs): LR-negative = 0.13 and LR-positive = 8.1. These different cut-off values create an intermediate range of 100–500 pg/ml with an LR-positive of only 1.9 pg/ml. Therefore, an intermediate BNP result alone cannot be used to rule in or rule out heart failure.25


LV inter-ventricular septum (IVS) and antero-lateral free wall (FW) were transmurally  analysed. LV glycogen content was shown to be increased in both DCM and ICM as compared with N hearts (P < 0.001), with a U-shaped transmural distribution . Capillary density was homogenously reduced in both DCM and ICM as compared with N (P < 0.05 versus N), with a lower decrease independent of the extent of fibrosis in sub-endocardial and sub-epicardial layers of DCM as compared with ICM. HIF1-α and nestin, recognized ischaemic molecular hallmarks, were similarly expressed in DCM-LV and ICM-LV myocardium. The proteomic profile was overlapping by ˜50% in DCM and ICM groups. Morphological and molecular features of MH were detected in end-stage ICM as well as in end-stage DCM LV, despite epicardial coronary artery patency and lower fibrosis in DCM hearts. Unravelling the presence of MH in the absence of coronary stenosis may be helpful to design a novel approach in the clinical management of DCM.Myocardial hibernation (MH) is a well-known feature of human ischaemic cardiomyopathy (ICM), whereas its presence in human idiopathic dilated cardiomyopathy (DCM) is still controversial. We investigated the histological and molecular features of MH in left ventricle (LV) regions of failing DCM or ICM hearts. We examined failing hearts from DCM ( Myocardial hibernation is a well-known feature of ICM. It is clinically characterized by depressed LV resting contractility and perfusion, and recovery of flow-function relations under stress , 2. Evenn = 11) or ICM (n = 12) eligible for and undergoing heart transplantation (HT) according to recent guidelines [n = 8, LV-EF >55%), with no history of cardiac disease, selected but not used for transplantation because of unexpected cardiac arrest after brain death. Baseline characteristics of N and HF patients are shown in Table The study population consisted of 23 patients with HF and end-stage DCM  with a broadband phased array transducer (2–4 MHz). All measurements were performed by an expert cardiologist in accord with the recommendations of the American Society of Echocardiography . We usedi.e. cytoplasmic , hob-nail (sub-sarcolemmatic) or granular (mainly peri-nuclear PAS-positive granules). The size of cardiomyocytes was measured in longitudinally sectioned myocytes at 40× magnification in a blinded fashion, as previously described [i) visible and round-shaped nuclei located close to the cell centre; and (ii) intact cellular basement membranes. The regional population of normo-, hypo-and hypertrophic cardiomyocytes was expressed as number of cardiomyocytes (106) per gram of cardiac tissue. Masson's trichrome staining was used to detect the interstitial fibrosis, defined as the collagen content determined in the interstitial spaces [To assess the patency of the epicardial coronary arteries, the hearts were grossly examined as previously described . In all escribed , 21; meal spaces  and to ml spaces .i.e., a structural protein of extracellular matrix in hibernated myocardium  [To detect apoptotic cardiomyocytes, we performed a co-staining of selected LV slides using either TUNEL assay or a mouse monoclonal antibody raised against human alpha-sarcomeric actinin  that is a marker of adult mature cardiomyocytes . We meas, Italy)  and huma, Italy) . Single Proteins were extracted from snap-frozen myocardial samples of IVS, which represents the most remodelled LV region in the beating failing heart . The memn = 5), DCM (n = 5) and normal hearts (n = 3) and analysed by Multidimensional Protein Identification Technology (MudPIT) approach, as previously described [Human frozen myocardium (5 mg) was collected from viable IVS of ICM . All quantitative variables are presented as mean ± SEM. One-way As shown in Table Periodic acid-Schiff staining revealed the presence of significant glycogen storage in a larger fraction of myocytes in either the LV-FW or the IVS of both DCM and ICM hearts, and undetectable PAS staining in healthy LV myocardium (data not shown). The zonal distribution of PAS-positivity was similar in the myocardial layers of both failing hearts groups, yet the extent of glycogen deposits in the LV-FW of ICM was higher than in the corresponding layers of DCM hearts Fig. A and B. As shown in Figure ex vivo coronary examination showed no significant stenosis in the epicardial coronary arteries of either DCM or normal hearts. A homogeneously reduced number of capillaries per cardiomyocyte were detected in all myocardial layers of ICM as compared with N , independently from the magnitude and distribution of myocardial fibrosis. Similarly, Nestin was detected in cardiomyocytes of failing DCM and ICM LV ; they were also shown to be associated with molecular features of ischaemic microenvironment. Similar hallmarks of chronic MH were also detectable in the corresponding LV regions of end-stage ICM hearts harvested from patients with flow-limiting, critically stenotic and diffuse lesions of the epicardial coronary arteries, and LBBB. The phenotype of chronic MH was more pronounced in ICM hearts that constituted the positive control group of this study. The lack of ischaemic microenvironment and MH phenotype in the explanted normal hearts allowed the exclusion of an ischaemic damage depending on the brain death time, surgical procedure or the cardiac allograft storage. These findings support the hypothesis that the long-term exposure of adult human myocardium to an ischaemic microenvironment triggers biochemical processes leading up to hibernation, by interfering on gene and protein myocardial expression and causing the typical histological alterations that altogether represent a compensatory mechanism aimed at maintaining myocardial viability despite reduced myocardial blood flow .The development of the chronic MH phenotype in HF patients is difficult to track, whereas the morphological features of chronic MH are well-established and characterized by PAS-positive cardiomyocytes, loss of cardiomyocytes by apoptosis, patchy reduction in Cx-43 content , hypertrophic and hypo-/atrophic cardiomyocytes, interstitial fibrosis, increased fibronectin and fibroblasts (vimentin-positive cells) .ex vivo regional characterization of chronic MH phenotype was never performed in full-thickness myocardial samples from human failing DCM hearts so far. This study is the first to show the patchy structural hallmarks of chronic MH in the myocardial layers of full-thickness myocardial samples collected from two different LV regions of failing human DCM hearts that are characterized by patent epicardial coronary arteries.Although imaging-based diagnostic tests identified viable and dysfunctional myocardium in LV regions of patients with end-stage DCM , 42, theThe myocardial extent of intracellular glycogen, a clinically relevant marker of MH detected by PAS staining , 14, shoThe main adaptive response to hypoxia/ischaemia observed in adult myocardium chronically exposed to ischaemic microenvironment is the re-expression of foetal genes that has been previously shown in failing adult LV as a result of chronic MH , 46.Nestin is a foetal intermediate filament and an endogenous inhibitor of apoptosis , which iA high number of hypertrophic cardiomyocytes were found in the LV viable myocardium of DCM hearts. Hypertrophic cardiomyocytes are considered a hallmark of cellular remodelling in response to apoptosis  and/or tOn the basis of the previous findings, we suggest that the chronic maintenance of the MH phenotype was strictly dependent on the presence of an ischaemic microenvironment even in DCM hearts.Even though the myocardial adaptive response to ischaemic microenvironment may also be independent of haemodynamic factors as a result of temporal changes of LV function , 50, theDespite established evidence of severe myocardial hypoperfusion , 13, 41 To elucidate the coronary microvascular response regardless of the presence of coronary lesions or capillary depletion in DCM hearts, we can suggest that chronic LV dyssynchrony following Cx-43 depletion, typical of patients with LBBB and severe contractile dysfunction , might aDespite a recent imaging study did not show consistent changes of myocardial blood flow in dyssynchronous failing heart of DCM patients , we prevSimilar to the abovementioned hallmarks of MH, the regional loss of Cx-43 was also smaller in the end-stage DCM compared with ICM hearts.To better define the chronic MH phenotype in human end-stage DCM, we performed a detailed proteomic characterization of full-thickness samples collected from IVS, which is the LV region mainly affected by structural remodelling in the dyssynchronous failing heart  and by bOur study did not provide direct information as to the relationship between histological and functional features of explanted hearts. Finally, the limited sample size of patients without LBBB precluded a comparative analysis between DCM patients with and without LBBB. Then, further investigations are mandatory to better define if the abovementioned histological and morphometric changes might be related to the chronic nature of the HF more than to the mechanisms of chronic MH.ex vivo analysis.Structural features of chronic MH that is typical of ischaemic chronic HF were identified in the LV of patients with end-stage DCM undergoing HT, associated with evidence of ischaemic micro-environment and dyssynchronous substrate. Our investigation provides new data by a multimodal In conclusion, unravelling the basic molecular mechanisms leading to MH in DCM hearts may be helpful to identify novel pharmacological targets to halt the progression of remodelling towards HF, especially in patients not responsive to conventional treatments.