There is a need to standardise non-invasive measurements of liver iron concentrations (LIC) so clear inferences can be drawn about body iron levels that are associated with hepatic and extra-hepatic complications of iron overload. Since the first demonstration of an inverse relationship between biopsy LIC and liver magnetic resonance (MR) using a proof-of-concept T2* sequence, MR technology has advanced dramatically with a shorter minimum echo-time, closer inter-echo spacing and constant repetition time. These important advances allow more accurate calculation of liver T2* especially in patients with high LIC.Here, we used an optimised liver T2* sequence calibrated against 50 liver biopsy samples on 25 patients with transfusional haemosiderosis using ordinary least squares linear regression, and assessed the method reproducibility in 96 scans over an LIC range up to 42 mg/g dry weight (dw) using Bland-Altman plots. Using mixed model linear regression we compared the new T2*-LIC with R2-LIC (Ferriscan) on 92 scans in 54 patients with transfusional haemosiderosis and examined method agreement using Bland-Altman approach.-1.014. This yielded LIC values approximately 2.2 times higher than the proof-of-concept T2* method. Comparing this new T2*-LIC with the R2-LIC (Ferriscan) technique in 92 scans, we observed a close relationship between the two methods for values up to 10 mg/g dw, however the method agreement was poor.Strong linear correlation between ln(T2*) and ln(LIC) led to the calibration equation LIC = 31.94(T2*)New calibration of T2* against liver biopsy estimates LIC in a reproducible way, correcting the proof-of-concept calibration by 2.2 times. Due to poor agreement, both methods should be used separately to diagnose or rule out liver iron overload in patients with increased ferritin. The measurement of liver iron concentration (LIC) is clinically useful because LIC reflects total body iron in a predictable way. ChangesA variety of non-invasive methods have been used to measure LIC including liver susceptometry (SQUID),,12, T2-wThe T2* MR sequence was developed to measure myocardial iron, but in the first description and initial validation of the use of myocardial T2*, the relation between liver T2* and LIC (measured by biopsy) was documented. The incSince the initial T2* method was described, there hFor the calibration analysis we retrospectively studied 25 patients with transfusional hemosiderosis, including 20 Thalassemia Major, 2 Diamond-Blackfan Anemia, 2 Congenital Sideroblastic Anemia, 1 Pyruvate Kinase Deficiency Anemia, in whom 50 liver biopsies were undertaken at UCLH as part of clinical iron chelation studies on deferasirox; patientsFor comparison of T2*-LIC with R2-LIC, 92 scans were performed in 54 patients enrolled in the deferasirox EPIC study and moni31 healthy volunteers were invited to participate in the study. IRB approval was granted to the study and all patients and healthy volunteers signed informed consent forms before undergoing scans or liver biopsy. The study was approved by the Royal Brompton and Harefield Research Ethics Committee.Biopsy LIC was measured in a single central laboratory in Rennes, France  on paraffin embedded sections as previously described,22. Brie-1 with R2*[s-1] =1000/(T2*[ms]). Liver R2* in healthy volunteers (n = 31) was 37.0 ± 1.1 s-1 (mean ± SEM), SD 6.1 s-1, range 28.7 to 54.4 s-1.All MR scans were performed on a 1.5 T Sonata MR scanner  using a 4-channel anterior phased array coil at Royal Brompton Hospital, London (RBH). A transverse slice through the centre of the liver was imaged using a multi-echo single breath-hold gradient echo T2* sequence with a range of echo times (TE 0.93-16.0 ms). T2* was measured using Thalassemia Tools  from a region of interest (ROI) in an area of homogeneous liver tissue, avoiding blood vessels and other sources of artefact. To correct for background noise, a truncation method was used for curve fitting  sequences were obtained on the same scanner according to the EPIC study protocol, as reviewed recently.http://www.graphpad.com, and STATA Ver 10.1 .Replicated measurements were averaged for regression purposes however treated separately to estimate inter-observer reproducibility. For inter-observer liver R2* agreement, 96 liver R2* scans from 38 patients were independently evaluated in triplicate by two observers as described above Figure  and anal-1. Bias was negligible at 0.61%, 95% limits of agreement (LoA) were approximately 8 and 9% below and above the bias, corresponding to about 1.5 mg Fe/g dw in each direction (see Equation 1). This was considered clinically acceptable, especially for mean liver R2* values <400 s-1 where the inter-observer agreement was robust with the spread nearly limited to the 95% CI of the bias only.On difference-versus-mean Bland-Altman analysis Figure , there w- 1.014 (Equation 1) with r-squared = 0.89, which for 5 ms corresponds to 6.24 mg/g dw (95% CI 5.67 to 6.88 or 91-110%) and for 2 ms to 15.82 mg/g dw (14.46 to 17.31 or 91-109%). Therefore the early T2* method[In total, 50 data pairs  were available for analysis on 25 patients. Median biopsy-to-scan window was 78 days . LIC values ranged from 1.7 to 42.3 mg/g dw (median 12.6). Nesting effect of patients was insignificant and did not warrant a mixed model regression approach. T2* and LIC showed curvilinear relationship  LIC value as its T2* equivalent of 5 ms in the T2* model. Because parameter estimation by unconstrained regression showed larger standard error of the intercept than in the T2* model, further analysis was performed using the calibration Equation 1. Due to the nature of the reciprocal relation between T2* and R2*, a greater intercept error is introduced when R2* is derived from T2* and compared to liver iron. For this reason, we have chosen to use T2* for our calibration.With T2* values expressed as R2* (=1000/T2*), the relationship initially looked linear, however non-normally distributed residuals and heteroscedasticity (fanning-out effect) prevented both linear and non-linear LSR analysis , but showed a weak significant relationship between LIC and staging of fibrosis  to mean LIC: slope 1.99, r-squared 0.18, p < 0.001). In view of the latter, we examined whether exclusion of stage 4 and 5 data pairs altered the calibration equation, however differences in absolute sum of squares for both models were insignificant (p > 0.82) therefore no changes to Equation 1 were made (data not shown).We have also examined whether excluding data pairs with large biopsy-MR window alters the LIC to T2* relationship, and have therefore compared a linear model based data with a median window of 28 days  with Equation 1, however there was no significant difference between absolute sum of squares .The LIC values obtained with the above recalibrated T2* method were compared with LIC values obtained using the R2 (Ferriscan) method in 92 scans performed in 54 patients. The median time window between the T2* and R2 scan was 13 days (range 0 to 91). R2-LIC values were measured across the entire clinically relevant range from 1.0 to 43.3 mg/g dw . T2*-LIC values ranged from 1.25 to 41.10 mg/g dw . Data pairs were also restricted to those obtained within 30 days and the two data sets compared (not shown), however there was no significant difference in the regression line or the data scatter between the two sets.whole range relationship could not be described by linear LSR unless the data were log-transformed. Mixed model regression of the log-transformed data (significant patient nesting effect p < 0.001) showed ln(R2-LIC) = 1.04 × ln(T2*-LIC)-0.08, exponentiated to (R2-LIC) = 0.93 × (T2*-LIC)1.04. The best-fit line closely follows the line of identity (95% CI of both constants includes 1), however confident prediction of higher values is impossible due to increasing scatter, which is supported by low explained variance (r-squared = 0.65) and lack of agreement in the whole range Bland-Altman plot . Given that the slope is indistinguishable from 1, this essentially shows an identity relationship between the two methods within the limited range. However percentage difference Bland-Altman plot for this range still shows poor agreement even after linear correction for non-uniform scatter  for T2*-LIC was 0.37 mg/g dw over this range (0-10 mg/g dw), as calculated from within-subject variance (one-way ANOVA with patient as group). IRC canNon-invasive assessment of LIC is increasingly used as an alternative to biopsy and in order for clinicians to have evidence-based guidelines for the management of iron overload, it is important that LIC measurements are comparable across studies, treatment centres and continents. Recently, considerable effort has been undertaken to standardise the assessment of myocardial iron with T2* across centres internationally,26, but A less widely appreciated reason for why further calibration is necessary is that biopsy LIC, the so-called ‘gold standard’ for LIC determination, is also not standardised and highly variable. The variability of needle biopsy LIC is dependent on the biopsy specimen size CV of aD, we wisBecause the calibrations in this paper were retrospective, utilising MRI data obtained during routine testing, and biopsy samples obtained as part of chelator studies,,4 the ti-1 or LIC ≈ 15 mg/g dw  methodology at a single centre (RBH). This has been achieved with two independent observers, each choosing the ROI to examine in triplicate, and by then comparing the intra-observer mean liver R2* between the two observers . This IOR is acceptable over a wide range of R2*, being particularly good for R2* < 500 s-1 predicted a mean LIC of 8 mg/g dw with 95% prediction bands from approximately 3 to 12 mg/g dw, while for 600 s-1 15 (9–20)mg/g dw, respectively[Wood et al., 300 s-1 relates to mean LIC of 8 mg/g dw, with prediction bands between 4.5-12, while for 600 s-1 – to 16.5 (12.5-20) mg/g dw.IRC-derived variability of T2*-LIC constitutes 19% of the variability between R2-LIC and T2*-LIC represented by the 95% LoA interval Figure D. Other ectively. Hankinsectively examinedOur data show higher LIC values for similar R2* than those quoted in the above two papers Figure  and the In conclusion, the R2* method described in this paper shows near-linearity to biopsy LIC values over a wide clinical range. There is good inter-observer reproducibility, however it is not possible to know to what extent the decrease in reproducibility at high LIC values is a consequence of the inhomogeneity in liver iron obtained by biopsy and to what extent this is a reflection of the T2* measurements, but this phenomenon has also been noted with the R2 Ferriscan technique and SQUID. Differences from other R2*/T2* derived LIC calibrations may be explained by differences in post-biopsy sample processing and fitting algorithms. Poor agreement between T2*LIC and R2LIC, even at low magnitude is not derived from ROI- and reproducibility-related variability of both methods but likely stems from different sensitivity of R2 and R2* to iron distribution and noise sources.CI: Confidence interval; CV: Coefficient of variability; dw: Dry weight; IOR: Inter-observer reproducibility; IQR: Inter-quartile range; IRB: Institutional Review Board; IRC: Inter-observer repeatability coefficient; LIC: Liver iron concentrations; LoA: Limits of agreement; LSR: Least squares regression; MR: Magnetic resonance; RBH: Royal Brompton Hospital; ROI: Region of interest; SD: Standard deviation; SEM: Standard error of the mean; SIR: Signal intensity ratio; SQUID: Superconducting quantum interference device; TE: Echo time; TR: Repetition time; UCLH: University College London Hospitals.MG, JC, MR, MA, JP declare no relevant conflicts of interest. GS has consultancy agreement with Novartis. TH has received honoraria from Novartis, Apotex and AMAG, DP is a director and stockholder of Cardiovascular Imaging Solutions, London, UK and a consultant to Novartis, ApoPharma, Siemens, Bayer, AMAG and Shire.MG, DP and JP designed the study, and wrote the manuscript. MG recruited subjects and analysed the data. JC, GS, MA, and TH performed and analysed the scans, and reviewed the manuscript. TH developed the T2* measurement model. MR (study statistician) performed the regression analyses and reviewed the manuscript. All authors read and approved the final manuscript.


Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. However, diagnosis of intraventricular dyssynchrony in patients with AF is difficult due to beat-to-beat variation. Additionally, evaluation of mechanical dyssynchrony in the traditional method is based on average of 5 to 10 beats, which is exhausting and time consuming. Single-beat evaluation of a beat with equal subsequent cardiac cycles has been proposed as an accurate method in patients with AF.We proposed to evaluate intraventricular mechanical dyssynchrony by measuring time-to-peak systolic velocity between basolateral and basoseptal segments  using Tissue Doppler Study (TDI) by two different methods.31 patient (68 ± 10.3 years) with heart failure (EF < 35%) and AF rhythm, R-R cycle length more than 500 msec were evaluated. We found a target beat in which preceding R-R (R-R1) to pre-preceding R-R (R-R2) ratio was 1(RR1/RR2 = 1) then measured the intraventricular dyssynchrony in that cycle. Intraventricular dyssynchrony was also determined and averaged for 8 consecutive cardiac cycles. The values at RR1/RR2 = 1 were compared with the average of intraventricular dyssynchrony in eight cycles and the relationship between dyssynchrony were evaluated by paired T-test, linear Pearson correlation (r2), linear regression analysis.The average of dyssynchrony in eight cycles showed a positive correlation with dyssynchrony in target beat RR1/RR2 = 1. Average of dyssynchrony in target beat was 46.77 msec, and average of 8 cycle was = 47.701, .Measurement of intraventricular dyssynchromy in basoseptal and basolateral segments in AF and heart failure patients in a single beat with RR1/RR2 = 1 , were very similar to the average value of eight cardiac cycle. Cardiac resynchronization therapy (CRT) has emerged as an established therapy for patients with systolic heart failure (HF), low ejection fraction (EF) and prolonged QRS duration and who had received optimal drug treatment , 2. CRT The purpose of this study was to evaluate and determine the use of single single-beat with equal subsequent cycle and to assess LV dyssynchrony in patients with HF and AF.Upon approval by the Ethics Committee in our research center, 31 patients with heart failure and atrial fibrillation were prospectively enrolled in this 6-month study. The inclusion criteria were congestive heart failure, class III-IV of New York Heart Association (NYHA) LV systolic dysfunction (EF ≤ 35%) and R-R cycle lengths longer than 500 milliseconds. We excluded patients with other causes of non-sinus rhythm, prosthetic valve disease and complete atrioventricular block. In addition, patients who had poor acoustic windows were excluded. Written informed/release consents was obtained from all patients. All patients underwent a standard 12-lead electrocardiography and echocardiographic examination for specific evaluation of intraventricular dyssynchrony. Heart rates were maintained between 60 and 100 beats/ min, during echocardiography.The standard method with 12-lead electrocardiograms was used, at a paper speed of 25 mm/s and a scale of 10 mm/mV. QRS period duration were measured . Two electrophysiologists assessed the QRS morphology and their diagnosis was considered final. They were blinded to the clinical status of the patients.The patients were imaged in the left lateral decubitus position using a commercially available system  equipped with a 2.5-MHz phased array transducer. Left ventricular end-systolic, end-diastolic volumes and LV ejection fractions were assessed by biplane Simpson's method and graded according to established ASE/EAE guidelines. The images were obtained with a sweep speed of 100 cm/s, with gains and filters optimized. TDI was performed from 2-chamber, 4-chamber, and apical long axis views with an optimal Doppler insonation angle to assess myocardial regional function. TDI measurements were obtained from two different methods. At first, 3, 5 and 8 consecutive beats were stored digitally. The digital cine loops were analyzed using off-line analysis. We calculated mean of 3, 5 and 8 beats based on first beat. In the second method, we found a target beat in which preceding R-R (R-R1) to pre-preceding R-R (R-R2) ratio was 1 (RR1/RR2 = 1). Beats with R-R interval difference less than 5% of the mean have been considered as RR1/RR2 = 1 , then weThe interval from the beginning of Q-wave to the maximum positive velocity during the ejection period was defined as time to peak systolic velocity . IntraveSPSS 15 for Windows  was applied for all analysis. Characteristic variables were expressed by mean ± standard deviation (SD), frequency, and relative frequency for scale and categorical variable respectively. Agreement between the calculated value of LV systolic dyssynchrony at R-R1/R-R2 and the measured average value of dyssynchrony in 3,5 and 8 consecutive cardiac cycles evaluated by using Bland and Altman plot in the linear regression line. P values of < 0.05 were considered statistically significant.Thirty-one patients (13 (42%) female, mean ± SD of age 68.35 ± 10.3 years) were enrolled in this study. Mean ± SD of LVEF was 22.74 ± 6.738. Mean ± SD of LVES was 137.48 ± 47.724 and mean ± SD of LVED was 173.42 ± 51.905. The most common cardiac diagnosis was coronary artery disease in 23patients (74.2%), 3 patients (9.7%) had dilated cardiomyopathy, 2 patients (6.5%) had hypertrophic cardiomyopathy and 3 patients (9.7%) had valvular heart disease.The parameters of left ventricle systolic dyssynchrony (SLWD) during AF showed a significant positive correlation between the R-R1 interval and the averaged value of 3, 5 and 8 consecutive cardiac cycles. There were no significant difference between the target beat and the averaged value of 3, 5 and 8 consecutive cycles. There was an increasing trend in correlation coefficient between the target beat and the averaged value of 3, 5 and 8 consecutive cycles with the increasing in the number of beats . The regThis study demonstrated that in AF rhythm, intraventricular dyssynchrony in a single beat with RR1/RR2 = 1 is quite similar to the average value of 8 cardiac cycles. Intraventricular mechanical dyssynchrony is characterized by abnormality in the movement of different LV walls due to delayed electrical conduction . It has The mean number of cardiac cycles required in AF is more than that in sinus rhythm, this is both difficult and time consuming. Dubrey et al. showed that the mean number of cycles necessary to assess cardiac output in AF was three times that needed in sinus rhythm . Further


Previous studies observed the phenomenon of high signal intensity on T2 -weighted image of cardiac magnetic resonance imaging (CMR) in hypertrophic cardiomyopathy(HCM). However, the underlying histopathologic mechanism is unclear. Elevated cardiac troponin can be detected in some HCM patients. A reasonable hypothesis is that myocardial T2-high signals is a potential marker of myocaridal injury in HCM. We sought to investigate the association between cardiac troponin and the extent of T2-high signals in HCM patients.Forty-four HCM patients underwent 3.0T CMR scanning. On T2-weighted images, the number of segments with high-signal intensityand the percentage of high-signal area (>2 SD above remote tissue) were measured in 16 myocardial segments along the LV mid-myocardial circumference on 3 short-axis images. The level of high sensitivity cardiac troponin T(hs-cTnT) was also assessed.,s test showed the percentage of myocardium with T2-high signal significantly associated with the hs-cTnT levelMyocardial T2-high signals were indentified in 33(75%)patients and 144(20.5%) segments.Elevated hs-cTnT was observed in 28(63.6%)patients.Cochran-Armitage test showed a statistically significant trend of increasing level of hs-cTnT with elevating number of segments with myocardial T2-high signal (p=0.002).Then,PearsonMyocardial T2-high signals can be considered as a marker of myocardial injury in HCM patients.


We sought to evaluate the impact of ischemic burden for the prediction of hard cardiac events  in patients with known or suspected CAD who undergo dobutamine stress cardiac magnetic resonance imaging (DCMR)We included 3166 patients (pts.), mean age 63±12 years, 27% female, who underwent DCMR in 3 tertiary cardiac centres . Pts. were separated in groups based on the number of ischemic segments by wall motion abnormalities (WMA) as follows: 1. no ischemic segment, 2. one ischemic segment, 3. two ischemic segments and 4. ≥three ischemic segments. Cardiac death and nonfatal myocardial infarction were registered as hard cardiac events. Pts. with an “early” revascularization procedure (in the first three months after DCMR) were not included in the final survival analysis.Pts. were followed for a median of 3.1 years (iqr 2–4.5 years). 187 (5.9%) pts. experienced hard cardiac events. 2349 (74.2%) had no inducible ischemia, 189 (6%) had ischemia in 1 segment, 292 (9.2%) in 2 segments and 336 (10.6%) ≥3 segments. Patients with only 1 ischemic segment showed a high rate of hard cardiac events of ∼6% annually, which was 10-fold higher compared to those without ischemia  but similar to those with 2 and ≥3ischemic segments .The presence of inducible ischemia even in a single ‘culprit’ myocardial segment during DCMR is enough to predict hard cardiac events in patients with known or suspected CAD. Estimating the risk of subsequent cardiac events is of paramount importance in patients with known or suspected coronary artery disease (CAD), because an invasive therapy is warranted for patients with myocardial ischemia who are at high-risk for future events Stress induced myocardial ischemia exhibits significant prognostic information in this population cohort, surpassing the prognostic value of conventional atherogenic risk factors The extent of ischemia was shown to carry prognostic value in patients undergoing DSE. In this regard, patients with ≥3 segments with WMA exhibit high-risk for subsequent cardiac events In this respect, the aim of our study was to determine whether (i) the extent and (ii) the localization of inducible myocardial ischemia in terms of WMA during high-dose dobutamine stress cardiac magnetic resonance (DCMR) are decisive for the prediction of cardiac events and future revascularization procedures.http://www.medizinische-fakultaet-hd.uni-heidelberg.de/Ethikkommission.106025.0.html) specifically approved our study . Written informed consent was obtained from all patients before the DCMR examination.The study was conducted in accordance with the standards of our local ethics committee . Our institutional review board  enrolled in 3 tertiary cardiac centres  were evaluated using DCMR between January 2000 and June 2008. Examinations were performed using 1.5-Tesla (Heidelberg and Berlin) and 3.0-Tesla (London) clinical whole-body CMR-scanners. The referral to DCMR was done according to the available recommendations at the time the study was carried. In this regard, the referring physician evaluated the pretest probability of the patient, and depending on the results of the stress ECG and other factors (i.e. echogenic windows of the patient) the patient was referred for a DCMR examination.Patients with unstable angina, sub-acute myocardial infarction (within 1 month prior to DCMR), severe arterial hypertension (>200/120 mmHg), moderate or severe valvular disease and general contraindications to CMR  were excluded.3104 patients of our cohort have been reported in previous studies 2) were recorded at the time of the DCMR. History of CAD encompassed angiographically significant CAD (≥50% lumen narrowing), prior infarction and prior coronary revascularization by PCI or CABG.Traditional risk factors for CAD, including arterial hypertension (blood pressure ≥140/90 mm Hg or antihypertensive therapy) Cardiovascular MR-images were acquired at rest and during a standardized high-dose dobutamine protocol 2, matrix of 256×256 pixels, slice thickness of 8.00 or 10.00 mm, flip angle of 50 degree, time to echo of 1.82 ms, and time to repeat of 3.65 ms. Temporal resolution was 25 to 50 ms. A 4-, 2-, and 3-chamber and 3 short-axis views  were used for wall motion assessment at baseline and were repeated during each stage of stress, including the peak level inotropic stimulation. Dobutamine was infused intravenously during 3-minute stages, at incremental doses of 10, 20, 30, and 40 µg/kg of body weight per minute until at least 85% of the age-predicted heart rate was reached. If at the peak dose of dobutamine infusion the target heart rate was not achieved, atropine was administrated in 0.25 mg increments up to a maximal dose of 2.0 mg. Stress testing was discontinued when the target heart rate was achieved, or when one of the following occurred: new or worsening WMA in at least one myocardial segment, severe chest pain or dyspnea, decrease in systolic blood pressure of ≥40 mmHg, severe arterial hypertension (blood pressure 240/120 mmHg), or severe arrhythmias. In the absence of ischemia, failure to attain 85% of age-predicted maximal heart rate was considered as a non-diagnostic result.The heart was imaged according to the recommendations of the Society for Cardiovascular Magnetic Resonance using a balanced, fast-field echo sequence with parallel imaging  For interpretation of wall motion, corresponding rest and peak stress cine images were displayed using View Forum software . Seventeen myocardial segments were evaluated at rest and during stress according to AHA guidelines, and wall motion was graded visually using a 4-point scale  Patients were categorized in four groups based on the number of segments involved, as follows: (i) no ischemia, (ii) 1 ischemic segment, (iii) 2 ischemic segments and (iv) 3 or more ischemic segments.Patients were grouped based on the numbers of coronary territories involved: (i) 1 coronary territory, (ii) 2 coronary territories and (iii) 3 coronary territories.This was performed only in patients with one ischemic territory. For this analysis patients were categorized according to inducible ischemia in the LAD versus LCX or RCA perfusion territory.Personnel unaware of the stress results contacted each subject or an immediate family member (in case of death) and the date of this contact was used for calculating the follow-up time duration. The day of the DCMR examination was considered the start of the follow-up period. Cardiac death and nonfatal myocardial infarction (MI) were registered as hard cardiac events. Cardiac death was defined as death caused by 1) intractable heart failure, 2) acute myocardial infarction, or 3) sudden cause presumably due to infarction or severe arrhythmia. Myocardial infarction was defined by angina of 30 minutes duration and either ST segment elevation of ≥2 mm in 2 consecutive ECG leads or a rise in cardiac enzymes (i.e. troponin T of ≥0.03 µg/l). Other cardiac events included clinically indicated revascularization by PCI or CABG. Hereby, the decision for PCI or CABG was left at the discretion of the referring physician. Because the results of the MR-examination may have triggered coronary revascularization, patients with ‘early’ revascularization within 3 months after DCMR were censored at the time of such revascularization procedures. For patients with an ‘early’ revascularization procedure, a separate analysis was performed to test for the effect of the revascularization procedure on outcomes.t-tests or repeated-measures ANOVA with Bonferroni correction for multiple comparisons were used to compare continuous variables. Group differences between ordinal variables were tested using the exact Mann-Whitney test, and differences between nominal variables were assessed using Fisher exact tests. All tests were 2-tailed. In a random subset of cases (n = 150) cine images were re-read by observers blinded to patient identity, clinical and other CMR data (S.K. and G.K.). Agreement between blinded observers and clinical reads for the interpretation of wall motion was calculated using k-statistics. To evaluate the association of the studied parameters with the endpoint, a univariate analysis encompassing the demographic, clinical and CMR-derived parameters was performed. Subsequently, a Cox proportional regression multivariate analysis model with a backward approach with deletion of the least significant variable until all variables had a p<0.1 was generated. Interaction tests were performed to analyze the relationship between presence of ischemia and early revascularization procedures and the extension of ischemia and early revascularization procedures, respectively. Kaplan-Meier curves were used in order to estimate the distribution of cardiac events as a function of the follow-up duration and to calculate the annual rates for cardiac events and revascularization procedures. Statistical analysis was performed using MedCalc 9.3  computer program. P-values of <0.05 were considered statistically significant.Continuous variables are expressed as mean ± standard deviation, while categorical variables are expressed as median and interquartile range. Unpaired Student Patients were followed for 3.4±1.8 years . 187 (5.9%) patients experienced cardiac death and myocardial infarction . 2349 (74.2%) patients had no inducible ischemia. From the 817 (25.8%) patients with inducible WMA, 189 patients (6%) had ischemia in 1 segment, 292 (9.2%) in 2, and 336 (10.6%) in 3 or more segments. Patients with one ischemic segment exhibited a significantly higher yearly rate of hard cardiac events (∼6%), compared to those without inducible ischemia (∼0.6%) but similar to those with ischemia either in 2 (∼5.5%) or at least 3 (∼7%) myocardial segments during DCMR . Thus, t614 (19.4%) patients showed inducible ischemia in 1, 189 (6%) in 2 and 14 (0.4%) in all 3 coronary territories. Of 614 patients who had inducible ischemia in only one coronary territory, 197 (32%) were related to the LAD, 229 (37%) to the LCX and 188 (31%) to the RCA territory.Interestingly, the analysis by ischemia localization revealed a higher rate for cardiac death and MI in patients with inducible ischemia within the LAD territory . In addiFrom the 512 patients who had an early revascularization procedure, 79 (15.4%) showed ischemia in one territory, 134 (26.1%) ischemia in two territories and 158 (30.8%) in three or more territories. 141 Patients underwent an early revascularization procedure despite negative DCMR.Neither the extent nor the localization of myocardial ischemia by DCMR influenced the proportion of patients who underwent an early revascularization procedure .Patients benefited in terms of outcome from early revascularization procedures only if they displayed ischemia on DCMR , the benAs illustrated in Agreement between observers interpreting CMR data in terms of inducible WMA during clinical reads versus blinded reads on a patient level was 94% .Our findings in 3166 patients within 3 tertiary centers with high-volume imaging departments demonstrate that:(i). The presence of inducible ischemia in only 1 ‘culprit’ myocardial segment during DCMR is sufficient to predict cardiac death and MI in suspected and known CAD.(ii). Ischemia within the LAD territory is associated with poorer outcomes.(iii). Patients benefit from early revascularization procedures even in the presence of ischemia restricted to 1–2 segments. Conversely, patients without ischemia by DCMR do not benefit from revascularization.The prognostic role of various non-invasive imaging modalities including DSE, nuclear scintigraphy and DCMR in patients with CAD is clinically established In our study we demonstrated in a large cohort of over 3000 patients, that even a single segment of the myocardial circumference exhibiting ischemia during DCMR translates in a much higher rate of cardiac death and MI. The presence of ischemia in two or more segments however, did not further enhance the associated risk for future events, compared to patients with ischemia in a single myocardial segment. DCMR was significantly associated with outcomes both in patients with suspected and known CAD. Importantly, in contrast to previous nuclear and echocardiography studies an association between ischemic burden and outcomes could not be established, as any evidence of ischemia was predictive of markedly enhanced risk. On the other hand, myocardial perfusion during DCMR was not systematically analysed in our study, which is a limitation. However, the assessment of myocardial perfusion is still challenging with increasing heart rates during dobutamine due to motion artefacts. In addition, with current standard perfusion protocols, less myocardium can be visualized, so that ischemia in regions like the apical cap or the true basal inferior wall may be missed. These shortcomings, however, may be circumvented by the recent availability of multichannel cardiac coils, which may allow for 3D first-pass perfusion scans.Furthermore, a recent comparison of DSE and DCMR showed the latter to be a more robust predictor of adverse outcome, which could be explained by the better spatial resolution of CMR resulting to a lower likelihood for false positive results compared to DSE Analysing by ischemia localization we found a higher likelihood of cardiac events in patients with inducible WMA in the left anterior descending territory. Our findings are in agreement with previous reports, where a higher rate of adverse cardiac events was noticed in patients with angiographically significant LAD stenosis compared to significant lumen narrowing in other coronary vessels In our study, early revascularization procedures reduced cardiac event rates in patients with inducible ischemia in ≥1 myocardial segments, which is in agreement with recent CMR trials Our study had an observational character, and DCMR results were not used in order to structure patient treatment in a blinded or randomised way. In this regard, clinicians had full access to the results of stress testing, which obviously triggered early revascularization procedures in a large percentage of patients with inducible ischemia. However, subsection analysis showed that neither the extent nor the localization of ischemia influenced the referral of patients to an early revascularization procedure. Although patients who underwent such early revascularization procedures were censored from analysis at this time point we cannot exclude some influence to our results due to referral or selection biases. Moreover patients were not randomly assigned to undergo invasive versus medical therapy, which may have influenced the obtained results due to selection biases.In our observational study, one single myocardial segment with inducible wall motion abnormality during DCMR is sufficient to predict hard cardiac events and revascularization procedures in patients with known or suspected coronary artery disease. Furthermore, LAD territory related ischemia is associated with a worse prognosis compared to the other coronary territories. Patients with inducible ischemia benefit from coronary revascularization even in case of ‘mild extent’ ischemia in 1–2 myocardial segments, whereas those without ischemia do not benefit from coronary revascularization and should therefore be treated conservatively.


A relationship between myocardial fibrosis and ventricular dysfunction has been demonstrated using late gadolinium enhancement (LGE) in the pressure-loaded right ventricle from congenital heart defects. In patients with Eisenmenger syndrome (ES), the presence of LGE has not been investigated. The aims of this study were to detect any myocardial fibrosis in ES and describe major clinical variables associated with the finding.From 45 subjects screened, 30 subjects  underwent prospective cardiovascular magnetic resonance with LGE to quantify biventricular volume and function as well as maximal and submaximal exercise during a single visit. Standard cine acquisitions were obtained for ventricular volume and function. Further imaging was performed after administration of 0.1 mmol/kg gadolinium contrast. Regions of LGE were evaluated qualitatively and quantitatively by manual contouring of identified areas, with total area expressed as a percentage of mass. Patients were followed prospectively (mean follow up 7.4 ± 0.4 years) and any deaths recorded. Patients with LGE findings were compared to those without.LGE was present in 22/30 (73%) patients, specifically in RV myocardium (70%), RV trabeculae (60%), LV myocardium (33%) or LV papillary muscles (30%), though in small amounts . Those with any LGE were not different in age, history of arrhythmia, desaturation, nor hemoglobin, nor ventricular size, mass, or function. Exercise capacity was low, but also not different between those with and without LGE. Similarly no significant associations were found with amount of fibrosis. There were five deaths among patients with LGE, versus two in patients without, but no difference in survival .Myocardial fibrosis by LGE is common in ES, though not extensive. The presence and quantity of LGE did not correlate with ventricular size, function, degree of cyanosis, exercise capacity, or survival in this pilot study. More data are clearly required before recommendations for routine use of LGE in these patients can be made. Eisenmenger syndrome (ES) is a multisystem disorder. In addition to other vulnerable organs, myocardial dysfunction can occur from long-standing pressure loading and cyanosis, and heart failure is a common cause of eventual death . As suchThrough several studies, LGE has been demonstrated in various congenital heart disease subgroups including those with tetralogy of Fallot, transposition of the great arteries, and following a Fontan palliation -6. ColleTherefore, as part of a large prospective cohort study of Eisenmenger patients, we sought to define the prevalence and extent of LGE in ES and explore meaningful associations with other clinical or functional parameters and survival. We hypothesized that LGE would be more prevalent in patients with more cyanosis and ventricular dysfunction, and that it would portend worse survival.Consecutive adults with ES, defined as a known intracardiac or extracardiac shunt with increased pulmonary vascular resistance and reversed or bi-directional shunt resulting in hypoxemia at rest, were invited to participate. Subjects were excluded for acute decompensated heart failure, active hemoptysis, recent surgery, or non-elective hospitalization, but were invited to participate after resolution of the event. Subjects with contraindications to CMR were excluded, including those with impaired renal function (creatinine > 1.5 mg/dl) who were ineligible for gadolinium contrast. Other elements from this prospective descriptive study have been previously reported ,10. The CMR was performed using a 1.5 Tesla scanner  with a phased array body coil. After standard initial localizers and long-axis acquisitions using steady-state free precession, short-axis cine images (7 mm with 3 mm spacing) were obtained from base to apex. Volumes of the right ventricle (RV) and left ventricle (LV) at end-diastole and end-systole, indexed to body surface area, were calculated by contouring the epi- and endocardial borders from short axis images. Contouring included trabeculae and papillary muscles as part of the myocardial mass, per our standard protocol [LGE imaging was obtained 5–20 minutes after 0.1 mmol/kg IV gadolinium-DTPA  administration. Multiple short-axis slices from base to apex were acquired using a segmented fast low-angle shot inversion recovery sequence  as employed in other projects [Images were analyzed offline using CMR tools  with contrast/brightness settings adjusted for uniform dark signal from normal myocardium. Images were compared to cine images in the same plane to ensure that small regions of enhancement were not areas of pooled gadolinium between trabeculae. LGE was defined as an area of increased signal within myocardium equal or greater to blood pool signal. Confirmation was obtained by comparing images with altered phase/frequency-encoding direction. Location and two-dimensional area of each region of enhancement were recorded. Total area was multiplied by slice thickness to give volume of LGE, converted to mass expressed as a percentage of total myocardial mass, similar to methods employed previously . Enhance2), carbon dioxide production (VCO2), anaerobic threshold, peak VO2, and ventilatory efficiency slope (Ve/VCO2).All participants completed a sub-maximal 6-minute walk test. Distance walked was recorded in meters . PatientPatients received follow-up at Royal Brompton Hospital, where detailed records were available for each. All patients were accounted for at the time of final analysis. For deceased patients, date of death and cause of death were obtained. Otherwise, date of last known clinical follow-up was recorded. Other standardized data in follow-up were not obtained.Analysis was done using SPSS for Windows 11.0. Continuous variables were compared with student’s t-test, while categorical variables were compared by chi-square or Fisher’s exact test. Non-normal variables (brain natriuretic peptide) were compared using the Mann–Whitney U test. Univariate regression was done using Pearson’s correlation coefficient. Results were expressed as mean ± SD or median/interquartile range, with p < 0.05 considered statistically significant. Variables associated with survival were identified using Kaplan-Meier analysis, though low numbers of events limited more in-depth analysis of survival.Of 61 Eisenmenger patients screened, 45 patients met all inclusion/exclusion criteria for MRI scanning. From these 30 were successfully studied with LGE. Clinical and laboratory details are provided  and RV mass correlated with LV mass , with RV ejection fraction slightly lower than LV Figure , left. AAll patients were accounted for in follow-up (mean follow-up 7.4 ± 0.4 years for living patients). The longest duration of follow-up was 8.4 years. There were seven deaths total, five among patients with LGE present, two in patients without LGE findings. In addition there were three deaths in those who did not complete the LGE portion of the scan. Of those studied with LGE, three died of heart failure, but only one of these had detectable LGE. Two others died of non-cardiac causes (bladder carcinoma and acute abdomen). In two more the cause of death was unknown. The presence of LGE in any form did not differentiate survivors from non-survivors . Kaplan Meier curves are shown (Figure The use of any imaging technique should be driven primarily by its ability to direct management decisions, inform disease mechanisms or estimate prognosis. Studies in congenital heart disease have demonstrated that LGE is associated with poorer functional class, ventricular volume and function, exercise capacity and arrhythmia -6,13. InIdentification of fibrosis demonstrates susceptibility to this final common pathway of ventricular dysfunction, particularly of the RV. Both chronic cyanosis and pressure loading likely contribute to various signaling pathways leading to myofibroblast activity that causes fibrosis -16. FibrThere are several plausible explanations for the lack of association between LGE and clinical variables in this study. First, our sample was small. Although the study enrolled a limited number of patients, all data were acquired prospectively, and the cohort reflected the wide range of ES with long follow-up. While it is certainly possible that a larger sample size may show statistical differences, our data suggest that such differences may be small, even clinically insignificant. Despite the relatively smaller sample, we followed our patients for a considerably longer period of time compared to other studies, looking for clinical endpoints that may be related to the presence of fibrosis even in a small study. Yet after eight years of follow-up we could not show a meaningful association.Second, while fibrosis is certainly present, it is likely more diffuse . In perfThird, our methods of quantification may have been overly sensitive, suggested by our high prevalence of relatively small areas of fibrosis. Our initial aim was to be inclusive of any type of enhancement, not knowing whether clinical significance would be found. Images were acquired and interpreted by trained, experienced imagers, and we are reasonably confident in our ability to avoid artifacts, etc. Still, image quality can at times be limited, and interpretation was largely subjective. We specifically excluded enhancement due to blood pooling within trabeculae or RV-LV junctional enhancement due to hypertrophy , recogniFinally but perhaps most relevant to clinical practice, ES is a multi-organ disease, with many different causes of clinical symptoms, exercise capacity, and death. Fibrosis likely only plays a small role in the overall clinical trajectory of the patient. In fact, there were several non cardiac related deaths, and of the three patients with CHF-related death, two had no detectable LGE. Thus, it is possible that even in a larger population the presence of dense fibrosis in ES may still not have a demonstrable association between LGE and function or survival.An additional novel finding from our study was that the RV and LV were morphologically and functionally similar, Mass and volume were linearly related; the LV had a proportionately larger mass, mostly due to inclusion of the septum. LGE was present in both ventricles but more abundant in the RV. The similarity of the two ventricles is congruous with the understanding that both face similar loading conditions from birth due to the shunt. The RV mass does not diminish in the postnatal period following a fall in pulmonary vascular resistance as occurs in those without shunts. Furthermore, the LGE data demonstrated fibrosis in both ventricles, not just the adversely loaded RV, as we have demonstrated in other conditions . This isOur study confirms the presence of myocardial fibrosis in ES, particularly in the morphologic RV, as found in smaller series . Small aWe note that CMR can offer valuable information for ES including clarification of anatomy, ventricular function, measurement of flow/shunts, and inspection of the pulmonary arteries including detection of thrombi . HoweverAlthough LGE is common in ES, it appears to be of limited extent, particularly in the RV. LGE did not correlate with functional capacity, severity of shunt or cyanosis, ventricular size or function, or arrhythmia in this study. Its routine application cannot be recommended at present by our pilot data. Further studies inclusive of measuring diffuse fibrosis in ES are warranted.CMR: Cardiovascular magnetic resonance; ES: Eisenmenger syndrome; LGE: Late gadolinium enhancement; RV: Right ventricle; LV: Left ventricle.The authors declare that they have no competing interest.CSB: Study design, funding, ethics, subject consent, study execution, CMR interpretation and quantification, data analysis and interpretation, and primary manuscript author. SKP: CMR acquisition and interpretation, data interpretation and manuscript review. CC: CMR quantification including quantification of late enhancement areas. SVB: Subject recruitment, CMR acquisition, CMR interpretation, manuscript review. KD: Follow up data for survival, manuscript review. MAG: Study design, hypothesis generation, funding, subject recruitment, data and manuscript review. All authors read and approved the final manuscript.


Quantification of left ventricular (LV) size and function from CMR images relies on endocardial border delineation and selection of relevant short-axis (SAX) slices. Multiple border detection algorithms have been tested to replace subjective manual tracing. However, there are no widely accepted criteria which basal slices to include in the LV volume, and endocardial definition near the apex is often suboptimal, making this task challenging in many patients. We hypothesized that this could be solved by defining mitral annular (MA) plane and apex in the long-axis (LAX) views. Our goal was to test this approach in combination with automated endocardial border detection using conventional methodology as a reference.SAX images from 50 patients were analyzed using custom software to measure end-systolic and end-diastolic LV volumes  and ejection fraction (EF) from stacks of SAX images. The apex and insertion points of the mitral leaflets were manually marked on LAX views, and used to approximate MA plane at ED and ES. Automated measurement of LV volumes was guided by including in the LV cavity only slices or parts of slices located between MA plane and the LV apex. Endocardial border was automatically detected using our previously described algorithm based on a probabilistic level set approach guided by noise distribution. Endocardial boundaries were also manually traced by an experienced investigator to obtain reference values. To determine the main sources of inter-technique disagreement, 10 patients with largest errors were reviewed using combined 3D displays of the LAX and relevant SAX views with the MA plane.Selection of the anatomic landmarks in LAX views was possible in all 50 patients, allowing automated measurement of LV volumes without the need for subjective slice selection. Inter-technique comparisons resulted in high correlations , small biases (1 and 9 ml and -7%) and reasonable limits of agreement. 3D visualization showed that the worst inter-technique agreement was due to incorrect manual tracing at LV base that erroneously included parts of the atrium or excluded parts of LV cavity in 7/10 patients, and other reasons in the remaining 3 patients.Defining the MA plane and apex in the LAX views obviates the need for subjective decision on slice inclusion and LV cavity boundary delimitation in basal slices. When combined with automated endocardial boundary detection, it provides measurements of LV volumes and function that are potentially more accurate than the standard methodology.None.


Ebstein's anomaly consists of varying degrees of tricuspid dysplasia and displacement into the right ventricular (RV) cavity, along with changes in ventricular function predominantly affecting the RV. Measuring alterations in contraction pattern and dyssynchrony may provide insights into ventricular performance in this disease. We sought to quantify right and left ventricular (RV and LV) deformation and dyssynchrony in a cohort of patients with Ebstein's anomaly in comparison with normal controls using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT).Twenty-six patients with uncorrected Ebstein's anomaly and 10 normal controls were prospectively studied. LV and RV global longitudinal myocardial strain (GLSLV and GLSRV) and time to peak strain (TPKLV and TPKRV) were calculated from the 4-chamber cine CMR images. Intraventricular dyssynchrony (IntraVD) was calculated as the difference between the segments with the longest and shortest TPK divided by the global TPK value of the respective ventricle: (IntraVD) = TPKlongest-TPKshortest/TPK global. The ratio of global TPKRV and TPKLV was measured as interventricular dyssynchrony (InterVD).Mean patient age was 28 ± 15 . GLSRV was significantly reduced in patients (-15.7 ± 5.2) as compared to controls , while there was no significant difference in GLSLV or global TPKRV and TPKLV between patients and controls .


Nationally, symptomatic heart failure affects 1.5-2% of Canadians, incurs $3 billion in hospital costs annually and the global burden is expected to double in the next 1–2 decades. The current one-year mortality rate after diagnosis of heart failure remains high at >25%. Consequently, new therapeutic strategies need to be developed for this debilitating condition.http://albertaheartresearch.ca) is to develop novel diagnostic, therapeutic and prognostic approaches to patients with heart failure with preserved ejection fraction. We hypothesize that novel imaging techniques and biomarkers will aid in describing heart failure with preserved ejection fraction. Furthermore, the development of new diagnostic criteria will allow us to: 1) better define risk factors associated with heart failure with preserved ejection fraction; 2) elucidate clinical, cellular and molecular mechanisms involved with the development and progression of heart failure with preserved ejection fraction; 3) design and test new therapeutic strategies for patients with heart failure with preserved ejection fraction. Additionally, Alberta HEART provides training and education for enhancing translational medicine, knowledge translation and clinical practice in heart failure. This is a prospective observational cohort study of patients with, or at risk for, heart failure. Patients will have sequential testing including quality of life and clinical outcomes over 12 months. After that time, study participants will be passively followed via linkage to external administrative databases. Clinical outcomes of interest include death, hospitalization, emergency department visits, physician resource use and/or heart transplant. Patients will be followed for a total of 5 years.The objective of the Alberta HEART program (Alberta HEART has the primary objective to define new diagnostic criteria for patients with heart failure with preserved ejection fraction. New criteria will allow for targeted therapies, diagnostic tests and further understanding of the patients, both at-risk for and with heart failure.NCT02052804.ClinicalTrials.gov  While advancements in medical and surgical therapies have improved cardiac mortality, these advances have led to an increase in the incidence and prevalence of heart failure (HF), em, em14], Thus, our goal is to evaluate a wider array of imaging tests for the purpose of defining a new set of practical criteria for the characterization of diastolic dysfunction that would be widely available. In addition to standard measures, main features will be evaluated using one or both of echocardiographic and CMR imaging: (1) ventricular stiffness,25; (2) In brief, the CMR scans will be performed on a 1.5 T magnet  and will include an assessment of: (1) atrial and ventricular volumes and function using steady state free precession (SSFP), (2) myocardial tissue characterization using late gadolinium enhancement (LGE) as well as quantitative T1 and T2 imaging, (3) estimation of ventricular and vascular stiffness using SSFP, phase contrast and tagging techniques and (4) pulmonary water content. For LGE and T1 imaging, 0.15 mmol/kg of gadolinium contrast  will be given intravenously. Cardiac volumes and function and myocardial scar will be analyzed using commercially available software  by experienced interpreters blinded to the study group assignment. Other measures of cardiac function and myocardial tissue characterization as well as vascular function and pulmonary water content will be performed using custom built software (MATLAB).2D and 3D echocardiography will be performed on IE 33 (Philips) scanners with and without intravenous injection of the ultrasound contrast agent Definity. In addition, recordings using color, spectral, tissue Doppler and speckle tracking imaging will be obtained according to the American Society of Echocardiography (ASE). The following measurements will be performed by two experienced observers according ASE standards: LV volumes, ejection fraction, LA volumes, RV size and function, quantification of valvular lesions, systolic pulmonary artery pressure, mitral/tricuspid inflow velocities, mitral/tricuspid annular velocities, global longitudinal strain and strain rate. The recordings will also be processed using custom built software for fusion of 3D datasets and new tools to assess myocardial deformation which promise a more reliable assessment of volume changes as well as systolic and diastolic LV/RV function.2peak) that is due, in part, to impaired cardiovascular and skeletal muscle that results in reduced convective or diffusive O2 transport or decreased O2 utilization by the active muscles) to train researchers of all backgrounds and across all 4 pillars of research as described by the Canadian Institutes of Health Research  awarded in 2009. Additional funding is provided by NCE CECR Centre of Excellence for Prevention of Organ Failure and the Alberta Diabetes Institute. In-kind contributions were received from Capital Health Regional Authority  and the Alberta HEART investigators. JAE, JRBD, FAM, HJD, GDL, GYO and TJA receive salary awards from AI-HS. GYO receives salary awards from HSFC and CIHR. PEL holds the Charles A. Allard Chair in Diabetes Research. FAM holds the University of Alberta Chair in Cardiovascular Outcomes Research. MF holds the Hornstein Chair in Cardiovascular Imaging. HB holds the Heart & Stroke Foundation Endowed Chair for Cardiovascular Research. TA holds the Merck Frosst Chair in Cardiovascular Research, University of Calgary.All authors were involved in the conception and design of the research program. TJA, HB, AMC, HJD, JRBD, JAE, MJH, JGH, FAM, GYO, DIP and RBT contributed to the writing of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/91/prepub


T2 mapping indicates to be a sensitive method for detection of tissue oedema hidden beyond the detection limits of T2-weighted Cardiovascular Magnetic Resonance (CMR). However, due to variability of baseline T2 values in volunteers, reference values need to be defined. Therefore, the aim of the study was to investigate the effects of age and sex on quantitative T2 mapping with a turbo gradient-spin-echo (GRASE) sequence at 1.5 T. For that reason, we studied sensitivity issues as well as technical and biological effects on GRASE-derived myocardial T2 maps. Furthermore, intra- and interobserver variability were calculated using data from a large volunteer group.ex vivo and in vivo. The optimized parameters were used to analyse CMR images of 74 volunteers of mixed sex and a wide range of age with typical prevalence of hypertension and diabetes. Myocardial T2 values were analysed globally and according to the 17 segment model. Strain-encoded (SENC) imaging was additionally performed to investigate possible effects of myocardial strain on global or segmental T2 values.GRASE-derived multiecho images were analysed using dedicated software. After sequence optimization, validation and sensitivity measurements were performed in muscle phantoms Ex vivo studies in muscle phantoms showed, that GRASE-derived T2 values were comparable to those acquired by a standard multiecho spinecho sequence but faster by a factor of 6. Besides that, T2 values reflected tissue water content. The in vivo measurements in volunteers revealed intra- and interobserver correlations with R2=0.91 and R2=0.94 as well as a coefficients of variation of 2.4% and 2.2%, respectively. While global T2 time significantly decreased towards the heart basis, female volunteers had significant higher T2 time irrespective of myocardial region. We found no correlation of segmental T2 values with maximal systolic, diastolic strain or heart rate. Interestingly, volunteers´ age was significantly correlated to T2 time while that was not the case for other coincident cardiovascular risk factors.GRASE-derived T2 maps are highly reproducible. However, female sex and aging with typical prevalence of hypertension and diabetes were accompanied by increased myocardial T2 values. Thus, sex and age must be considered as influence factors when using GRASE in a diagnostic manner.The online version of this article (doi:10.1186/s12968-015-0118-0) contains supplementary material, which is available to authorized users. One of the major advantages of Cardiovascular Magnetic Resonance (CMR) in comparison to other non-invasive imaging modalities represents its superior soft tissue contrast. This contrast is determined by myocardial T1 and T2 relaxation properties which can be used for imaging myocardial diseases without the need of additional contrast enhancement [T2-weighted CMR has proven to be useful in discriminating acute from chronic myocardial infarct lesions according to the presence or absence of oedema . HoweverSeveral approaches to quantify myocardial T2 relaxation in a global manner have been set up in patients with ubiquitous myocardial diseases like familiar hypertrophy or Morbus Fabry -10. ReceAgainst this background, the present study evaluates a turbo gradient- and spin-echo (GRASE) sequence for quantification of local myocardial T2 values at 1.5 Tesla. To this end, 74 volunteers of different sex and a wide range of age were enrolled. We hypothesize that age and sex have an impact on myocardial T2 values.The ethical board of Heinrich Heine University Düsseldorf approved the present study (application number 4307). All participants were enrolled after informed consent was obtained. The study complies with the declaration of Helsinki.In total 74 volunteers were enrolled for the study. Depending on their age, two groups were formed  and compared in Table Phantom measurements as well as volunteer scans were performed using a 1.5 T scanner  with a 32-channel phased array coil.3, parallel imaging (SENSE) with an acceleration factor of 2, k-space data acquired with cartesian encoding scheme. For blood saturation a double inversion (black-blood) pulse was used.For T2 mapping we applied the GRASE sequence which has already been used for quantitative T2 measurement in liver and brain -20. ThisDetailed information about the phantom experiments can be found in the Additional file Besides validation purposes, the phantom study was set up to test the sensitivity of myocardial T2 quantification in terms of focal and global tissue water changes. In the first experiment, cow muscle (M. erector spinae) was cut into 15 small pieces of 20 g and 14 pieces were dehydrated by vacuum concentration  at given durations . All pieces of meat were imaged at once with GRASE. The percentage of tissue water was calculated as follows: the difference of wet weight to dry weight was divided by wet weight. This ratio (0.63) was constant between 20 and 24 h, indicating complete tissue drying and the relative tissue water mass of the meat to be 63%. This value was set to 100% of tissue water.3, 35 phases, breath-hold), T2-weighted imaging in the respective SAX , GRASE in the respective 3 SAX , and strain-encoded imaging in two chamber view (2CH), 4CH and the respective SAX . Older volunteers (>35 years), enrolled in our regular ambulance, additionally received Gadolinium DTPA  for myocardial stress-testing and LGE. The latter was performed using a 3-dimensional gradient -spoiled turbo fast field echo sequence with an nonselective 180° inversion-recovery pre-pulse-triggered to end-diastole which covered the whole ventricle .The measurement protocol was conducted in the following order: scout and reference scans, cine-loops in 3 short axis (SAX) slices and in four chamber view (4CH)  could be used as a goodness-of-fit parameter in order to exclude accidental values. If R2 was not within a tolerance interval chosen to be 0.7−1, the corresponding T2 value was not considered for further calculations. The resulting T2 constants were colour-coded using the spectral look-up table  were generated off-line using software based on the graphical programming language LabVIEW . An exponential decay curve was fitted to the intensity decline of each pixel within the images obtained from the multi echo sequence Figure A. The biEndo- and epicardial contours were manually drawn in reference images and automatically overlayed to the T2 map. Segmentation was done off-line using the same software as for the generation of T2 maps . For thicc/s) was used to measure early diastolic function and was calculated in 4 midventricular segments by dividing the change in strain between time frames by the temporal resolution (25 ms). Ecc/s was defined as the slope from end-systole to mid-diastole as has been previously published [To evaluate the role of wall movement on T2 values within the same segment, we acquired myocardial strain values by strain encoded imaging (SENC) of each myocardial segment analysed. Strains were derived from SENC images using dedicated software . Circumferential strain was calculated for 12 myocardial segments, not considering segments 2, 5, 8, 11, and 17. Peak systolic strain was defined as minimal strain value of all time frames, while peak diastolic strain was characterized as minimal strain value of all time frames following early diastolic relaxation. Early diastolic circumferential strain rate . Data were statistically analysed by the paired or unpaired Student’s ex vivo and found that GRASE derived T2 values were in good agreement with T2 values of a standard MESE in repeated experiments  to 150 ms (red). Mean myocardial T2 values were calculated automatically after drawing the myocardial contours as region of interest . As given in the figure, mean T2 value within myocardial tissue raised dependent on the number of echoes used for calculation. 15 echoes with an interecho spacing of 10 ms were found to cover the complete exponential decay of intensity in myocardial tissue. As can be seen in Figure In order to evaluate the effect of EPI on T2 values, we performed experiments in muscle-phantoms 74 volunteers whose characteristics are given in Table Figure For regional T2 analysis, 1056 segments were included. Here . However, myocardial strain rate during data acquisition was very low compared to early diastolic and systolic strain rate .Since myocardial aging was shown to be characterized by impaired relaxation properties , we compThe present study demonstrates the feasibility of myocardial T2 quantification with GRASE in a large cohort of volunteers. Our results indicate that T2 values are quite comparable between individual hearts with respect to segment location and sex. Interestingly, aging of the human heart with representative cardiovascular risk factors is significantly correlated with increasing myocardial T2 values and paralleled by diastolic relaxation impairment. On a segmental basis, however, maximal systolic or diastolic strain as measured by SENC imaging is not correlated to segmental T2 values.ex vivo while time saving by a factor of 6  compared to our female (55.0 ± 9.1 g/m2) volunteers (p < 0.05). While this finding would support increased T2 values in males compared to females as known for myocardial hypertrophy [In contrast to previous studies, our analysis revealed significantly increased T2 values in female compared to male volunteers. This was true for all slices in younger volunteers, while it was only observed by trend in aged volunteers without reaching the level of significance. Previous studies presumed higher T2 value variability in females due to increased cardiac motion . Howeverertrophy , we founMost interestingly, global myocardial T2 values of our study were positively correlated with age Figure . In lineThis study provides evidence, that in a large group of volunteers global myocardial T2 values were increased in female volunteers compared to male without a correlation to local strain values. Besides that, age was correlated with increasing T2 values. According to previous findings of myocardial T2 quantification, we found an apico-basal and anteroseptal-posterolateral gradient of T2 time in myocardial tissue. Against the background of the present findings we propose, that T2 reference values needs to be created for each type of sequence. This has to be performed with respect to age and sex for exact discrimination between healthy and diseased myocardium.


Background. Childhood cancer survivors treated with anthracyclines and mediastinal irradiation are at risk for late onset cardiotoxicity. Aims of the Study. To assess the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) and tissue Doppler imaging (TDI) as early predictors of late onset cardiotoxicity in asymptomatic survivors of childhood cancer treated with doxorubicin with or without mediastinal irradiation. Methods. A cross-sectional study on 58 asymptomatic survivors of childhood cancer who received doxorubicin in their treatment protocols and 32 asymptomatic Hodgkin's lymphoma survivors who received anthracycline and mediastinal irradiation. Levels of NT-proBNP, TDI, and conventional echocardiography were determined. Results. Thirty percent of survivors had abnormal NT-proBNP levels. It was significantly related to age at diagnosis, duration of follow-up, and cumulative dose of doxorubicin. TDI detected myocardial affection in 20% more than conventional echocardiography. Furthermore, abnormalities in TDI and NT-pro-BNP levels were more common in Hodgkin lymphoma survivors receiving both chemotherapy and radiotherapy. Conclusions. TDI could detect early cardiac dysfunction even in those with normal conventional echocardiography. Measurement of NT-proBNP represents an interesting strategy for detecting subclinical cardiotoxicity. We recommend prospective and multicenter studies to validate the role of NT-proBNP as an early marker for late onset doxorubicin-induced cardiotoxicity. Anthracyclines are widely used antineoplastic agents for the treatment of both childhood hematological malignancies and solid tumors, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin and Hodgkin's lymphoma, neuroblastoma, osteosarcoma, Ewing tumors, and nephroblastoma. Almost 60% of children with cancer receive anthracyclines as a part of their treatment . A majorCurrent monitoring techniques, such as MUGA (multigated acquisition scan) or echocardiography, have substantial limitations and detect LV dysfunction only after it had occurred. Cardiotoxicity is usually diagnosed only upon manifestation of clinical signs and symptoms or progressive cardiac dysfunction. Thus, new diagnostic tests are required to confirm ventricular dysfunction induced by anticancer therapy . It has This study aimed to assess the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) and tissue Doppler imaging (TDI) as early predictors of late onset cardiotoxicity in asymptomatic survivors of childhood cancer treated with doxorubicin with or without mediastinal irradiation.This cross-sectional study was carried out on 80 asymptomatic survivors of childhood cancer, who visited the late effects clinics of Pediatric Oncology, Zagazig University Hospitals, and late effects clinics of Pediatric Oncology, Benha Specialized Pediatric Hospital, during the period from January 2011 to December 2013. All children received doxorubicin as a part of their therapy for various kinds of malignancy for more than one year. Informed consent was obtained from the patients or their parents. Our inclusion criteria were patients in a stable general condition with no signs or symptoms of cardiac impairment at the time of evaluation and normal hepatic and renal function tests.Patients with history of cardiac diseases and hypertension were excluded from the study. The study was approved by the local ethics committee of contributing hospitals.Complete history taking and thorough physical examination including weight, body surface area (BSA), and measurement of blood pressure.The cumulative dose of anthracycline calculated for each patient according to his BSA.Methods for evaluation of subclinical cardiotoxicity.All survivors underwent all the following.(a) Conventional Echocardiography. Detailed conventional echocardiography was performed at Pediatric Cardiology Unit, Zagazig University Hospitals, using . Echocardiography was performed by a cardiologist who was blinded to the clinical details. Two-dimensional, M-mode, pulsed-wave (PW), and continuous-wave Doppler echocardiographic images were acquired. For all patients, standard measurements were left ventricular posterior wall thickness at diastole (LVPW), interventricular septum thickness at diastole (IVS), left ventricular dimensions at end-systole (LVES), and left ventricular dimensions at end-diastole (LVED). Shortening fraction (FS) and ejection fraction (EF) of the LV were calculated from M-mode measurements of LV dimensions at the level of mitral valve leaflets in parasternal long-axis view. Sample volume of the PW Doppler was placed between the tips of the mitral leaflets in the apical four-chamber view, and then diastolic functions of the left ventricle were measured . All measurements were compared with the normal values of LVPW, IVS, LVES, and LVED which were taken from the standard tables according to ages and BSA [ and BSA . An EF o and BSA . (b) Tissue Doppler Imaging (TDI). TDI was obtained according to the methods described by Kapusta et al. [a et al. . TDI stuS′), early diastole (E′), and late diastole (A′) was measured at the right and left ventricular free walls (RVFW and LVFW), respectively. Peak longitudinal myocardial velocities  were assessed within basal, middle, and apical parts of the right ventricular anterior wall and left ventricular posterior wall.In the parasternal, long-axis view measurements of peak myocardial velocities were made guided by color coded TDI. Peak myocardial velocity during systole ((c) NT-proBNP Analysis. Venous blood samples were obtained from an indwelling catheter after 30 minutes of rest in supine position. The blood samples were withdrawn into chilled tubes containing EDTA. The whole blood was centrifuged; plasma was decanted, immediately frozen, and stored at −27°C until assayed (within 6 months after sampling). Plasma concentration of NT-proBNP was measured by electrochemiluminescence immunoassay. It was performed with Modular E, using the NT-proBNP . The abnormal level was defined in our survivors based on age-dependent reference values by Albers and his colleagues [lleagues .t-test, Chi-square test (χ2), and Mann-Whitney U test. Probability (P) value was considered for statistical significance if it was less than 0.05.Data were analyzed using Microsoft Office 2007 (Excel) and Statistical Package for Social Science (SPSS) version 19.0.0, SPSS Inc., Chicago, IL, USA. Data were summarized using the arithmetic mean, standard deviation (SD), screening test, Studen's 2. Thirty-two patients (40%) had Hodgkin lymphoma, 27 patients (33.75%) had non-Hodgkin's lymphoma, and 21 patients (26.25%) had solid tumors   .P < 0.001). Abnormal NT-proBNP levels were associated with younger age of patients, longer duration of follow-up, and higher cumulative anthracycline doses  were not significantly related to abnormal NT-proBNP levels. E velocity was 115 ± 15 cm/s in abnormal NT-proBNP group versus 110 ± 13 cm/s in normal NT-proBNP group . E/A ratio was 1.91 ± 0.31 in abnormal proBNP group versus 1.83 ± 0.21 in normal proBNP group .Echocardiographic parameters were obtained from all 80 survivors. Twelve patients (15%) had abnormal echocardiography. Abnormal left ventricular systolic function (EF and FS) and diastolic function  of the studied children.E/E′) were positively correlated with cumulative dose of anthracyclines  was 8.18 ± 0.7 15 in abnormal NT-proBNP group versus 8.6 ± 0.6 in normal NT-proBNP group  and E/E′ was 14.06 ± 0.97 in abnormal NT-proBNP group versus 12.79 ± 1.03 in normal NT-proBNP group   .S′) (E′ and A′) velocities in all right ventricular free wall segments with P value < 0.001 in most of them. There was a significant relation between abnormal NT-proBNP and myocardial velocities of LV posterior wall. S′ ; meanwhile there was no significant difference in E′ velocity of apical and basal parts of LV posterior wall between both groups  free wall using color coded TDI. Patients with increased level of NT-proBNP had significantly low systolic (S′)  and diaswall. S′  and A′ vh groups .Our data showed a significant relationship between NT-proBNP and TDI parameters as all patients with increased serum level of NT-proBNP showed abnormalities in TDI, while only 4 out of 56 patients with normal level of NT-proBNP had abnormal TDI findings. None of patients with normal TDI showed high levels of NT-proBNP .P value < 0.001). Regarding diastolic function assessment in study groups, there was no significant difference in early diastolic velocity by routine echocardiography between exposed and unexposed groups. E velocity (cm/s) was 82 ± 10 versus 79 ± 11 in unexposed group ; however there was a highly significant difference between both groups regarding diastolic function by TDI. E′ velocity (cm/s) was 5.7 ± 0. 8 in exposed group versus 8 ± 1.1 in unexposed group  and E/E′ ratio was 14.38 ± 0.92 in exposed group versus 9.87 ± 1.32 in unexposed group   of different segments of LV posterior wall and RV anterior wall using color coded TDI were significantly lower in the exposed group  and exposed group (32 patients who received both chemotherapy and radiotherapy). Our data showed that the level of NT-proBNP was significantly higher in the exposed group when compared with the unexposed group. NT-proBNP level was 144.3 ± 28.6 pg/mL in exposed group versus 115 ± 13.7 pg/mL in unexposed group ( 0.0001) . Compareed group .Anthracycline chemotherapy and mediastinal and neck radiation are the most common causes of therapy-related cardiovascular complications in childhood cancer survivors . The earOne of the main risk factors for anthracycline cardiotoxicity is high cumulative dose which is associated with a higher incidence of subclinical cardiac dysfunction . In the E velocity in childhood cancer survivors exposed to anthracyclines [NT-proBNP has been shown to be a sensitive marker for heart failure in children in earlier studies –39. In pcyclines . In contcyclines  who coulS′, E′, and A′) in both LV and RV in some of our survivors in spite of normal routine echocardiography. Thus, TDI aberration was detected in hearts that appeared normal by routine echocardiography and might precede structural changes [S′, E′, and A′ velocities) of different segments of LV posterior wall and RV free wall using color coded TDI were significantly lower in the group exposed to both anthracyclines and mediastinal irradiation when compared to the group exposed to anthracyclines only. This is in agreement with the study done by Adams and Lipshultz who demonstrated that concomitant cardiac irradiation has been recognized as a risk factor of anthracyclines cardiotoxicity [TDI has been shown to be sensitive to identify anthracycline-induced cardiomyopathy and aberration in TDI parameters may be identified before abnormalities can be detected by conventional echocardiography . In our  changes , 47. Sim changes . Aberrat changes . Moreovetoxicity .E′) reflects the rate of myocardial relaxation, and it has been postulated as a good indicator of LV myocardial diastolic function. Normally, E/E′ at rest and during exercise (E/E′ < 8) are similar. Decreased mitral annular E′ is one of the earliest markers of diastolic dysfunction. In early diastolic dysfunction, TDI mitral annular early diastolic function (E′) is disturbed, whereas E velocity remains normal [E′ velocity in lateral mitral annulus with high E/E′ ratio in all cancer survivors with significantly higher E/E′ ratio in abnormal NT-proBNP group and the group exposed to combined chemotherapy and radiotherapy which suggest the role of TDI and NT-proBNP in early detection of late cardiotoxicity in childhood cancer survivors exposed to anthracyclines and in particular when combined with mediastinal irradiation. To the best of our knowledge, the only paper that studied the role of E/E′ ratio for detection of diastolic dysfunction in childhood cancer survivors exposed to anthracyclines was that done by Yildirim et al. who found a significant reduction in mitral septal annular early diastolic velocities E′ and elevation of mitral septal E/E′ values in a group exposed to anthracyclines [Analysis of TDI parameters in relation to NT-proBNP showed a significant relation between elevated NT-proBNP levels and TDI abnormalities. Similar results were reported by Sherief et al. and Yildirim et al. , 49. Tiss normal , 51. In


The aim of our current special issue was to present a series of original researches and reviews on recent advances in the diagnosis, medical therapy, and surgical approaches of heart failure.As reported in the introductive review of Agnetti et al., cardiovascular disease is the leading cause of mortality in the US and in westernized countries with ischemic heart disease accounting for the majority of these deaths. Paradoxically, the improvements in the medical and surgical treatments of acute coronary syndromes are leading to an increasing number of “survivors” who are then developing heart failure. Despite considerable advances in its management, the gold standard for the treatment of end-stage heart failure patients remains heart transplantation. Nevertheless, this procedure can be offered only to a small percentage of patients who could benefit from a new heart due to the limited availability of donor organs. The authors reported in this comprehensive review the evaluation of the safety and efficacy of innovative approaches in the diagnosis and treatment of patients refractory to standard medical therapy and excluded from cardiac transplantation lists.Among the studies included in this special issue, two of them investigated specific pathogenic aspects of heart failure. M. Kunin et al. studied the role of proinflammatory cytokines in congestive heart failure. In particular the authors evaluated the effect of peritoneal dialysis used in the long-term management of these patients on the peripheral-circulating levels of these cytokines. Interestingly, they found that peritoneal dialysis treatment caused a reduction in circulating inflammatory cytokines levels along with improvement in plasma markers of inflammation in patients with refractory chronic heart failure, concluding that this effect may be partly responsible for the efficacy of peritoneal dialysis for refractory heart failure.It is described that heart failure is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. To cast further light on this issue, A. Cabassi et al. investigated the relationship between plasma myeloperoxidase-related chlorinating activity, ceruloplasmin, and ferroxidase I and nitrosative stress and inflammatory, neurohormonal, and nutritional biomarkers in heart failure patients. This elegant study supported the conclusions that plasma myeloperoxidase chlorinated activity is increased in elderly patients who suffer from chronic heart failure and positively associated with ceruloplasmin and inflammatory, neurohormonal, and nitrosative parameters, suggesting a key role in heart failure progression.A major focus of studies on acute heart failure is the need for methods that allow the early detection of hemodynamic variables that can be a key prognostic role after cardiac surgery. F. Corradi et al. in their study investigated the Renal Doppler Resistive Index as a marker of oxygen supply and demand mismatch in 61 postoperative cardiac surgery patients. Interestingly, by multivariate analysis, Renal Doppler Resistive Index was significantly correlated with mixed-venous oxygen saturation, suggesting that, in mechanically ventilated patients after cardiac surgery, it could be used as a marker of early vascular response to tissue hypoxia.β, and elevated systemic NO levels. The authors have reported an exhaustive review of novel therapeutic strategies for reducing right heart failure associated mortality in fibrotic lung diseases, because only “an early, effective and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life.”We must not forget that there are many patients suffering from heart failure secondary to extracardiac diseases. Among the causes of heart failure, an important place is held by cardiotoxicity due to antineoplastic treatments that has emerged as a clinically relevant problem as a consequence of the relevant improvement of survival after cancer. In the last decade recent advances have emerged in clinical and pathophysiological aspects of left ventricular dysfunction induced by the most widely used anticancer drugs. M. Molinaro et al., in their comprehensive review entitled “Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs,” have particularly examined the role of early, sensitive markers of cardiac dysfunction, in order to predict this form of cardiomyopathy before left ventricular ejection fraction is reduced. It seems actually that this is increasingly important issue, along with the evaluation of novel therapeutic and cardioprotective strategies, to protect cardiooncologic patients from the development of congestive heart failure. As reported by A. Adegunsoye et al., there are also a consistent number of patients who die due to right heart failure and pulmonary hypertension secondary to fibrotic lung diseases. Significant factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-Another major focus of studies on acute heart failure is related to the evaluation of new surgical alternatives to transplantation or new systems or new materials available for future cardiac assist devices. In this special issue the review of J. Anand et al. explores the evolution of mechanical circulatory support and its potential for providing long-term therapy, which may address the limitations of cardiac transplantation. The innovation progresses have led to a solution of current challenges involving device complications. Moreover outcomes continue to improve and further data from both small and large registries help to advance evidence-based practices: thus patients in the most advanced stages of heart failure appear to have more hope than ever before. On the other hand the high costs, expanding indications, and rapidly increasing number of devices implanted will ultimately require important decisions to be made on the part of society, clinicians, and administrative agencies in order to establish the potential amount of economic resources to spend on this expensive, yet effective, therapy. Patient selection will remain paramount, although a very large population of patients will have the potential to benefit.In particular, K. Unthan et al. reported a study on the design and evaluation of a fully implantable control unit for blood pumps. It is well known that pneumatic devices sufficiently supply the patients with blood flow, although the patient's quality of life is limited by the percutaneous pressure lines and the size of the external control unit. General requirements for any implantable control unit are defined from a technical and medical point of view: need for a Transcutaneous Energy Transmission, autonomous operation, safety, geometry, and efficiency. The authors described the development of the control unit of the ReinHeart, a fully implantable Total Artificial Heart that, in validation tests, is demonstrated to be a stable operation with a promising good efficiency. Finally P. Morillas-Sendín et al. assessed the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device. The authors demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of a left ventricular assist device under conditions of partial support, giving interesting indications for the intensive pharmacological care of these high-risk patients.The modern approach to the diagnosis and treatment of heart failure is multidisciplinary and should be based on a close collaboration among researchers, clinicians, and cardiac surgeons particularly given that mandatory multiorgan attention is required in these high-risk patients.Future therapies for heart failure could include ventricular assist devices implantation or ventricular restoration techniques with the aim to obtain a reverse, positive remodeling in the unloaded heart. With an expanding “toolbox” of comprehensive basic, medical, surgical, and technological approaches, it is expected that these novel findings will soon be translated to the clinical practice. In fact, new therapeutic strategies are needed by the millions of patients suffering from heart failure. We hope that this special issue will help readers become familiarized with recent progress regarding the diagnosis and treatment of heart failure.