Unfavorable left ventricular (LV) remodelling may be associated with adverse outcomes after Tetralogy of Fallot (TOF) repair. We sought to assess T1 cardiovascular magnetic resonance (CMR) markers of diffuse LV myocardial fibrosis in children after TOF repair, and associated factors.In this prospective, cross-sectional study, native (=non-contrast) T1 times and extracellular volume fraction (ECV) were quantified in the LV myocardium using CMR. Results were related to ventricular volumes and function, degree of pulmonary regurgitation, as well as surgical characteristics, and exercise capacity.p < 0.05). In the patient group, higher native T1 and ECV correlated with higher Z-Scores of right and left ventricular end-diastolic volumes, but not with reduced left and right ventricular ejection fraction or higher pulmonary regurgitation fraction. Longer cardiopulmonary bypass and aortic cross clamp times at surgery correlated with increased native T1 times and ECVs . Maximum workload  correlated inversely with ECV . Higher native T1 times correlated with worse LV longitudinal  and mid short axis circumferential strain .There was no difference in native T1 times or ECV between 31 TOF patients  and 15 controls . Female TOF patients had higher ECVs than males (25.2 ± 2.9 % versus 22.7 ± 3.3 %, As compared to controls, TOF patients did not express higher markers of diffuse fibrosis. Longer cardiopulmonary bypass and aortic cross clamp times at surgery as well as biventricular enlargement and reduced exercise tolerance are associated with markers of diffuse myocardial fibrosis after TOF repair. Female patients have higher markers of diffuse myocardial fibrosis than males. While the vast majority of patients after repair for Tetralogy of Fallot (TOF) survive well into their adult years , there iLongitudinal relaxation or T1 times and extracellular volume fraction (ECV), measured with cardiovascular magnetic resonance (CMR), have been established as non-invasive markers of diffuse myocardial fibrosis . Both haThe aim of this study was to measure native T1 times and ECV in children after TOF repair, and to understand their potential origin and clinical significance.The cohort in this prospective, single-center study included patients with repaired TOF who underwent a non-sedated clinical contrast-enhanced CMR between March 2014 and January 2015. Patients with 'TOF type' double outlet right ventricle were included. Patients with pulmonary atresia and no major aortopulmonary collateral arteries were also included. Patients with pulmonary valve replacement following the initial complete repair and before CMR were excluded.Immediately prior to the CMR, blood was drawn to measure the hematocrit. Patients’ records were reviewed for demographic, clinical and surgical details. QRS duration was determined if an ECG was available within 6 months of the CMR. Echocardiograms performed within 6 months from CMR were reviewed for degree of tricuspid valve insufficiency, estimated right ventricular systolic pressure as assessed via the tricuspid regurgitation jet, tricuspid annular plane systolic excursion (TAPSE) and the peak gradient across the right ventricular outflow tract. Exercise test results were reviewed if performed within 6 months from CMR.Patients who underwent CMR for screening purposes for palpitations, non-specific chest pain, or family history of arrhythmogenic right ventricular cardiomyopathy served as controls, as long as the CMR and all other tests were normal.All CMR examinations were performed on a 1.5 Tesla scanner  using a phased-array multi-channel surface receiver coil. A modified Look-Locker inversion recovery sequence (MOLLI)  was usedThe presence of LV late gadolinium enhancement (LGE) was determined qualitatively on standard long-axis  and SA images using phase-sensitive inversion-recovery acquisitions ≥ 10 min after administration of the contrast agent (same injection as described above).Using the 8 raw images of the MOLLI sequence, native and post-contrast T1 times were measured by an experienced observer (ER), using commercially available software . Regions of interest were drawn in mid and basal SA in the interventricular septum, the LV free wall, the entire LV myocardium and in the LV blood pool, avoiding papillary muscles. If necessary, contours were adjusted in each phase. Myocardial contours comprised the central 2/3 of the myocardium, in order to avoid possible signal averaging with signal from blood or pericardial fat. For assessment of intra- and interobserver variability, all contours were redrawn by the primary as well as by a second observer in 15 randomly selected TOF patients.ECV was calculated using the following formula :\documenRV and LV volumes were measured from the stack of SA cine images in systole and diastole with calculation of ejection fraction. LV muscle mass was measured in diastole . RV muscle mass was measured in the patient group in diastole. Results were indexed to body surface area, and Z-scores for ventricular volumes and ejection fractions were calculated using published normative data .Cardiomechanics were measured using steady state free precession cine imaging and CMR feature tracking with commercially available software . The following parameters were assessed: Peak LV longitudinal strain and strain rate from 4-chamber view; circumferential strain and strain rate at the LV mid and basal SA levels, as well as LV torsion, calculated from rotation and ventricular dimensions as described elsewhere . PulmonaP values < 0.05 were considered significant.Data is described as means with standard deviations or medians with interquartile ranges (IQR) or frequencies as appropriate. Comparisons between groups (TOF patients and controls) and TOF subgroups were performed using Fisher’s exact test for categorical variables, and Student’s t-test for continuous variables, assuming unequal variance between samples (Satterthwaite methods). Associations of age, gender, heart rate, BSA, hematocrit and QRS-duration with T1 mapping results in TOF patients and controls were modelled in linear regression models (maximum likelihood method for parameter estimation). Pearson correlations were computed to assess associations between continuous variables. Variables with associations with fibrosis markers were entered into multivariable regression models for native T1 times and ECV. Intra- and interobserver variability for native T1 times and ECV were assessed using the Bland-Altman method. All statistical analyses were performed using SAS Version 9.3 . Thirty-six patients after TOF repair met the inclusion criteria. Five patients were excluded from the analysis: Two patients had undergone late repair at the age of 8 years and were regarded as non-representative of the current surgical era; one patient had a VSD patch leak with a residual shunt of Qp:Qs 1:5. T1 mapping images were non-diagnostic in two patients.Characteristics of the remaining 31 patients in comparison to 15 controls and surgical information of the patients are summarized in Table 2; LVESVi 44 ± 8 versus 37 ± 7 ml/m2; RVEDVi 159 ± 44 versus 129 ± 23 ml/m2; RVESVi 82 ± 26 ml/m2 versus 64 ± 14 ml/m2, all p < 0.05) and a higher RV muscle mass . There were no gender differences in ejection fraction of both ventricles and LV muscle mass in the TOF group. Female patients had been slightly younger at the time of repair (median age 3.8 (IQR 0.7–6.7) versus 7.4 .Results of CMR and echocardiography are shown in Table r = 0.52, p < 0.005). There was no correlation between RV and LV ejection fractions or between their respective Z-scores.In TOF patients RVEDVi correlated with LVEDVi (p < 0.05). Other cardiomechanical values  did not show significant differences.Mid SA circumferential strain was weaker in the patient group as compared to controls  had a higher percentage of predicted oxygen uptake at anaerobic threshold than females .QRS durations in TOF patients and controls are provided in Table p < 0.05; ECV mid SA 24.3 ± 3.7 % versus 22.3 ± 3.8 %, p < 0.05). These differences were not present in the control group.Native T1 times and ECV are listed in Table p < 0.05) and for ECV in all parts analysed . No patient had LV LGE.Female TOF patients had higher values as compared to male TOF patients for native T1 in the basal interventricular septum  and entire LV  at the base. Longer cardiopulmonary bypass time correlated with elevated native T1 time of the IVS , and with higher ECV of the entire LV  and IVS , all at the mid SA level. Longer aortic cross clamp time correlated with higher native T1 of the LV free wall in mid SA . In a multivariable analysis of age at surgery, cardiopulmonary bypass and aortic cross clamp times, longer bypass and cross clamp times were independently associated with elevated native T1 and ECV (in the regions described above). Patients who had undergone either a valve sparing or valved conduit repair had lower fibrosis markers than patients who had a transannular patch repair . Expectedly, pulmonary regurgitant volume was higher in the transannular patch group .Age at surgery correlated inversely with native T1 and ECV in the IVS  and ECV of the basal LV free wall .Maximal workload  correlated inversely with ECV of the entire LV in basal SA . There were no correlations of T1 mapping results with LV or RV ejection fraction or pulmonary regurgitation. Neither T1 times nor ECV correlated with RV systolic pressure or TAPSE by echocardiography. Worse  left ventricular 4-chamber longitudinal strain correlated with higher native T1 times . At the midventricular SA level, there was a weak correlation of higher native T1 times of the LV free wall and worse circumferential strain . There were no further correlations between T1 mapping (T1 and ECV) and myocardial strain, strain rate or torsion.Indexed ventricular volumes did not correlate with T1 mapping results. However, higher Z-scores of LVEDV, RVEDV and RVESV correlated with higher ECV in mid SA in all regions analysed (e.g., for entire LV I.On average, children and adolescents do not express CMR markers of increased amounts of LV myocardial fibrosis.II.Higher ECV is associated with larger LV and RV volumes.III.Longer cardiopulmonary bypass and aortic cross clamp times and younger age at primary surgical repair are associated with higher native T1 times and ECV.IV.The transannular patch approach is associated with higher markers of fibrosis than valve sparing techniques and valved RV to pulmonary artery conduits.V.Higher markers of diffuse fibrosis are associated with myocardial dysfunction and reduced cardiopulmonary exercise tolerance.Adult survivors after TOF repair have evidence of increased LV ECV, quantified by CMR T1 mapping , 15, 16.Although primarily a ‘right heart’ condition, LV dysfunction is not uncommon in TOF and a risk factor for adverse outcomes , 4. The Our previous pilot study suggested increased LV fibrosis in children with repaired TOF . HoweverRecently, a study in adults with repaired TOF found ECV to be associated with arrhythmia . An explWhether myocardial fibrosis causes impaired myocardial contractility remains to be clarified. In the patients studied here CMR markers of fibrosis were not related to LV ejection fraction, but higher ECV and native T1 were associated with decreased LV myocardial contractility, as evidenced by lower longitudinal and circumferential strain. These associations suggest that fibrotic remodelling does, indeed, translate into loss of myocardial function, even though the health of LVs of juvenile TOF patients is relatively preserved.T1 and ECV in different regions of the heart correlated with the various clinical parameters, likely due to the limited sample size, and the region with the highest diagnostic yield remains to be identified. Likewise, it is unclear whether ECV offers a diagnostic advantage over non-contrast native T1. It would be preferred to be able to avoid the use of gadolinium in light of concerns regarding possible gadolinium deposition in the brain  and nephOn average, children and adolescents after TOF repair do not express increased native T1 or ECV. Nonetheless, elevated CMR markers of LV fibrosis are associated with biventricular enlargement and LV myocardial dysfunction. Longer cardiopulmonary bypass and aortic cross clamp times appear to plant the seed for chronic fibrotic LV remodeling. Longitudinal studies are needed to inform us about the contribution of CMR T1 mapping to the prediction of outcomes in TOF patients.


Prenatal ultrasound screening has allowed for the detection of in utero cardiac abnormalities. Specifically, distinction is possible between ventricular diverticula and aneurysms, which is important because each condition has a different clinical outcome. We report the case of a 35-year-old, gravida 1, para 1 woman, with no significant past medical history, who underwent routine prenatal ultrasound screening at 32 weeks' gestation. A four-chamber ultrasound of the fetal heart combined with M-mode echocardiography showed abnormal dilatation of the right ventricular chamber measuring 2.2 cm × 1.0 cm but with normal contractility. Delivery was performed at full term by cesarean section, and a right ventricular diverticulum was confirmed by postnatal cardiac computed tomography. The baby developed normally with no cardiac sequelae during followup. This case demonstrates the importance of making a correct diagnosis of ventricular diverticula by prenatal ultrasound when abnormal dilatation of the fetal ventricle is identified during routine screening. Because evaluating the wall contractility by M-mode ultrasound leads to evaluating whether it has the myocardium, we conclude that M-mode echocardiography is effective for the purpose of prenatal cardiac diagnosis and can distinguish between ventricular aneurysms and functioning ventricular diverticula. Ventricular diverticula are rare, with an estimated incidence of 0.013% , and theVentricular diverticula are classified as muscular or fibrous , 5. The The 10-year survival rate of ventricular diverticula is approximately 80%, whereas the 4-year survival rate of ventricular aneurysms is approximately 30% . When anThis case involves a 35-year-old, gravida 1, para 1 mother with unremarkable medical and family histories. At routine pregnancy checkups, an abnormal fetal heart chamber was identified in the 32nd week of pregnancy and she was referred to our hospital in the 35th week of pregnancy. At that time, she was noted to have an abnormal heart chamber (2.2 cm × 1.0 cm) that was continuous to the front and outside of the right ventricle on four-chamber fetal ultrasound screening . The preThe subsequent course of the pregnancy was uneventful until term, when an elective cesarean section was performed in the 38th week because of a past cesarean section. A male infant was born weighing 2982 g, with an Apgar score of 8 at 1 min and 9 at 5 min and an umbilical arterial blood pH of 7.275. After the delivery, he was diagnosed definitively with a right ventricular diverticulum by the presence of myocardium in the abnormal heart chamber on computed tomography, with continued normal contraction Figures . His proGenerally, B-mode ultrasound is used for fetal screening, producing a grayscale picture that expresses the difference in acoustic impedance in black and white to indicate differences in “brightness.” This offers excellent visibility and is appropriate for observing the four-chamber view. However, the distinction between ventricular diverticula and aneurysms is difficult when using only B-mode ultrasound.When evaluating the wall thickness of the abnormal heart chamber by B-mode ultrasound, Peters et al.  proposedUltrasonography also includes the facility for M-mode imaging, in which the picture can display movement and change over time as the strength and weakness of the ultrasound beam's brightness on the same line continuously. In adults or newborns, echocardiography is frequently used to observe movement of the heart muscle and its valve, and it can determine whether there is myocardial contraction. Thus, it is possible that an abnormal heart chamber may be diagnosed as a ventricular diverticulum if normal contraction is present or a ventricular aneurysm if akinetic or dyskinetic contraction is present when evaluating the contractility of the abnormal heart chamber wall. In our case, the abnormal heart chamber was diagnosed prenatally as a ventricular diverticulum by confirming that the wall had normal contraction on M-mode ultrasound, which was later confirmed by postnatal computed tomography. Demir et al.  and OlorRecently, speckle tracking has been reported to be of value for assessing movement of heart walls . This te


Diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by LGE. Native and post-contrast T1 mapping in particular has shown promise as a novel biomarker to support diagnostic, therapeutic and prognostic decision making in ischaemic and non-ischaemic cardiomyopathies as well as in patients with acute chest pain syndromes. Furthermore, changes in the myocardium over time may be assessed longitudinally with this non-invasive tissue characterisation method.Cardiovascular Magnetic Resonance is increasingly used to differentiate the aetiology of cardiomyopathies. Late Gadolinium Enhancement (LGE) is the reference standard for non-invasive imaging of myocardial scar and  ECV on the other hand represents a physiological parameter and is derived from the ratio of T1 signal values. ECV values may therefore be more reproducible between different field strengths, vendors and acquisition techniques than both native and post-contrast T1 . ECV meaNative T1 and ECV help in the differential diagnosis of patients with acute chest pain including acute coronary syndrome, myocarditis and Takotsubo cardiomyopathy and can help in the distinction of acute from chronic infarction Fig. .Fig. 3Acmyocardial oedema (T2-weighted imaging), LGE in a mid-wall non-coronary pattern often in the infero-lateral wall, and hyperaemia/capillary leak  are present. Radunski et al. have performed a comprehensive comparison of the diagnostic accuracy of conventional CMR techniques and novel mapping techniques and demonstrated better diagnostic accuracy of T1 mapping and in particular by ECV ..38].Anderson-Fabry disease (AFD) is an intracellular lipid disorder  that causes concentric LV hypertrophy, heart failure and arrhythmias .intracellular  storage disease [On LGE images, AFD typically displays an infero-lateral mid-wall pattern of enhancement caused by focal fibrosis in this region. In addition, the low native T1 of fat can serve as an early surrogate marker of myocardial glycosphingolipid storage in AFD even before the development of LV hypertrophy . Native  disease  and ECV  disease  . Therefore, early iron deposition may be missed in these patients.Iron-overload develops primarily from increased absorption such as in genetic hemochromatosis or secondary to repeated blood transfusions, as in thalassaemia major . CardiacAutosomal dominant mutations involving sarcomeric genes lead to hypertrophic cardiomyopathy (HCM) and a combination of myocyte disarray, fibrosis and ventricular hypertrophy in distinct patterns . ClinicaLV or biventricular dilatation and systolic dysfunction without an obvious or detectable cause are the defining characteristics of dilated (nonischaemic) cardiomyopathy (DCM). In DCM, LGE typically occurs in a mid-wall pattern  but in tHeart failure is the final common pathway of many cardiomyopathies. Myocardial fibrosis – regardless of the aetiology – is a key mechanism in the development of diastolic and systolic heart failure. Since collagen deposition is often diffuse, LGE usually shows no regional fibrosis/scarring. According to data from the OPTIMIZE-HF registry preserved ejection fraction was present in a large proportion of patients with heart failure. Both heart failure patients with reduced and preserved ejection fraction experienced similar rates of mortality and morbidity . Su et aTissue characterisation by native T1 mapping may serve as an important source of diagnostic, therapeutic and prognostic decision making in various cardiac diseases.An advantage of a non-invasive method for the assessment of fibrosis is the potential to follow changes in the myocardium over time as in patients with cardiomyopathies or patients receiving cardiotoxic drugs. Patients with poor renal function  precluding gadolinium-based contrast injection may benefit from using native T1 mapping instead of LGE imaging. A clinical scenario where multi-parametric CMR tissue characterisation has already been established is in the assessment of patients with acute chest pain and no coronary artery disease. In such cases, tissue characterisation can assist in the differential diagnosis of micro-infarction, (peri-) myocarditis and stress cardiomyopathy (Takotsubo) and also other causes of diffuse fibrosis associated with high cardiac biomarker levels (such as high-sensitivity cardiac troponin).Clinically, several studies have shown that T1 mapping with ECV is particularly useful in the assessment of cardiac diseases with diffuse fibrosis. Furthermore, T1 mapping with ECV might be helpful as an adjunct in cases with ambiguous LGE. Beyond differential diagnosis of cardiomyopathies, tissue characterization with T1 mapping can be very useful in differentiating between pericardial fat vs. LGE, differentiating between epicardial fat vs. pericardial effusion as well as in tissue characterization of various cardiac tumours.More research is needed regarding the long-term prognostic impact of T1/ECV mapping, as well as its potential in therapy guidance of cardiac diseases such as heart failure, patients after heart transplantation as well as its role in valvular heart disease.Harmonization of acquisition protocols between vendors and institution will also be needed to allow wider adoption of the methods.Although tissue characterisation with native T1 and ECV has been shown to have incremental diagnostic benefit even in very early disease stages (e.g. diffuse fibrosis not detectable by LGE), there is an overlap between different cardiomyopathies and some overlap with normal T1 values. Like all medical parameters, abnormalities in native T1 and ECV need to be interpreted within their clinical context and pre-test probabilities and in conjunction with established CMR techniques such as LGE. Elevations and reductions of T1 and ECV are not specific and can be caused by various disease processes. In some instances, these processes can even cancel each other out .There is still some way to go with standardization of T1 mapping methods and protocols. Ongoing research for this purpose includes the use of standardized phantoms and software methods. For now, normal and pathological T1 values will largely depend on the acquisition scheme and will have to be defined in individual CMR centres.


Regional contractile dysfunction is a frequent finding in hypertrophic cardiomyopathy (HCM). We aimed to investigate the contribution of different tissue characteristics in HCM to regional contractile dysfunction.We prospectively recruited 50 patients with HCM who underwent cardiovascular magnetic resonance (CMR) studies at 3.0 T including cine imaging, T1 mapping and late gadolinium enhancement (LGE) imaging. For each segment of the American Heart Association model segment thickness, native T1, extracellular volume (ECV), presence of LGE and regional strain (by feature tracking and tissue tagging) were assessed. The relationship of segmental function, hypertrophy and tissue characteristics were determined using a mixed effects model, with random intercept for each patient.P < 0.001 for all) but not ECV. LGE  had a significant association with circumferential strain measured by tissue tagging.Individually segment thickness, native T1, ECV and the presence of LGE all had significant associations with regional strain. The first multivariable model  demonstrated that all strain parameters were associated with segment thickness  and native T1  but not LGE.In a second multivariable model  all strain parameters were associated with both segment thickness (Impairment of contractile function in HCM is predominantly associated with the degree of hypertrophy and native T1 but not markers of extracellular fibrosis (ECV or LGE). These findings suggest that impairment of contractility in HCM is mediated by mechanisms other than extracellular expansion that include cellular changes in structure and function. The cellular mechanisms leading to increased native T1 and its prognostic significance remain to be established. Hypertrophic cardiomyopathy (HCM) is commonly defined as a disease of hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic cause . VariousHCM is most commonly caused by mutation in genes encoding proteins within the unit of myocardial contraction, the sarcomere . The mecPrevious studies predominantly performed with echocardiography speckle tracking have shown that there is widespread variation in myocardial contractility throughout the ventricle in HCM. Regional impairment of contractility is predominantly related to the extent of hypertrophy and presence of replacement fibrosis , 7. CurrUsing CMR it is also possible to assess the tissue characteristics of the HCM phenotype. After administration of gadolinium based contrast agent, which is exclusively extracellular, late gadolinium enhancement (LGE) imaging allows identification of areas of focal fibrosis. Histological validation has suggested that the presence of LGE in HCM reflects replacement fibrosis , which iLGE is a qualitative technique relying upon contrast between tissue with and without fibrosis, and is therefore of limited use in the detection of diffuse fibrosis. For this purpose T1 mapping techniques are used that give a quantitative pixel-wise map of myocardial T1 values. This can be performed without contrast (native T1), or by measuring both pre and post contrast T1maps to compute pixel-wise map of extracellular volume fraction (ECV %) . ECV hasIt is presently unknown which tissue characteristics are associated with contractile dysfunction in HCM. We therefore planned to assess native T1, ECV and LGE segmentally and quantify their association with strain measured in the same segment. This would provide insight into the pathological processes that lead to impaired contractility in HCM.N = 30) were also recruited. The diagnosis of HCM was made independently by clinicians in keeping with current guidelines and based upon imaging including CMR, ECG, exercise testing, family history and genetic testing if possible [Fifty consecutive patients with HCM were prospectively recruited from the local Inherited Cardiovascular Conditions Service between August 2014 and August 2015 and healthy controls  and were planned using the 3 of 5 method [3, tag separation 7 mm, ≥18 phases, typical TR/TE 5.8/3.5 ms, flip angle 10°, typical temporal resolution 55 ms) was acquired in the same three short axis slices in 34/50 patients. Left ventricular volumes were obtained from cine imaging covering the entire LV in the short axis: balanced steady state free precession (SSFP), voxel size 1.2 x 1.2 mm2, slice thickness 10 mm with no gap, 50 cardiac phases. Left atrial (LA) volumes were obtained from cine imaging covering the entire heart in the transverse axis: balanced SSFP, voxel size 1.2 x 1.2 mm2, slice thickness 6 mm with no gap, 50 cardiac phases. 0.15 mmol/Kg Gadovist (Bayer Schering) was delivered by power injector  as a single bolus via a cannula placed in the ante-cubital fossa followed by 20 ml saline flush. Typical parameters for LGE were TR/TE 3.5/2.0 ms, flip angle 25°, acquired spatial resolution 1.54x1.76x10mm3 and performed in 10-12 short axis slices with ≥3 long axis orientations and phase-swapped acquisitions if indicated. Post contrast T1 mapping, using the same 5b (3 s) 3b MOLLI scheme as for native T1 mapping, was carried out in the same three slices exactly 15 min following last contrast injection (as above).All subjects underwent an identical CMR protocol performed on a 3.0 Tesla Philips Achieva TX system  equipped with a 32 channel cardiac phased array receiver coil. A full blood count, including haematocrit was measured at the time of intravenous cannulation. The cardiac long and short axes were determined using standard scout views. Basal, mid and apical pre-contrast (native) short axis T1 maps were generated using a validated Modified Look Locker Inversion (MOLLI) protocol   and inTag  by two physicians blinded to clinical data. LV mass, end diastolic volumes (EDV), end systolic volume (ESV) and LV ejection fraction (EF) were measured from short axis cine images excluding papillary muscles and trabeculations. Native and post contrast T1 relaxation time of myocardium and blood pool were measured from the three scanner generated T1 maps by contouring a region of interest in each segment of the 16 segment American Heart Association (AHA) model . ECV wasFor tagging analysis endocardial and epicardial contours were drawn on the short axis SPAMM sequences. Peak circumferential strain was measured for each segment of the AHA model using inTag . Strain was measured in the mid-myocardial layer  which has previously been reported to be the most reproducible .Segments were defined as hypertrophied if the maximal thickness was ≥15 mm in keeping with current guidelines . ReplaceT test or Mann Whitney U test used as appropriate. A mixed effects model with random intercept for each person was used to assess the association between Ecc-FT, Err-FT and Ecc-SPAMM and segment thickness, native T1, ECV and LGE. For each patient 16 segments with each parameter were included in the model to include segments with varying degrees of phenotypic expression. This model was used to account for the fact that segments from the same patient may not behave independently. The association between each strain parameter and segment thickness, native T1, ECV and LGE was tested using a two multivariable mixed effects model with random intercept adjusting for all three independent variables. ECV is not statistically independent from native T1 and therefore separate multivariable models were tested for each. Results are reported as mean ± standard deviation. P < 0.05 was considered statistically significant.Statistical analysis was performed using Stata 14 . Continuous variables are expressed as means ± standard deviation (SD). Categorical variables are expressed as N (%). Shapiro-Wilk test was used to test normality then unpaired Fifty patients with HCM were recruited. Patient characteristics are shown in Table Controls were 36.2 ± 11.6 years old and 22 (73%) were male. From these controls the normal range for native T1 was 1190 ± 24.7 ms and ECV 24.3 ± 2.6%. Therefore segments with native T1 > 1239.4 ms and ECV > 29.5% (+2 SD) were defined as abnormally elevated.P < 0.001 for all), Table The presence of hypertrophy, LGE, raised native T1 and raised ECV were all associated with impairment of all Ecc-FT, Err-FT and Ecc-SPAMM (P < 0.001). In multivariable model 2  both segment thickness  P < 0.001) and native T1  P < 0.001) had significant association with Ecc-FT.On univariable analysis segment thickness, LGE, native T1 and ECV all had a significant association with Ecc-FT, Err-FT and Ecc-SPAMM, Table P < 0.001) and native T1  P < 0.001) had significant association with Err-FT.In multivariable model 1 only segment thickness had a significant association with Err-FT , P < 0.001). In multivariable model 2 both segment thickness  P < 0.001) and LGE , P = 0.024) had a significant association with Ecc-SPAMM. In multivariable model 2 both segment thickness  P < 0.001) and native T1  P < 0.001) but not LGE had significant association with Ecc-SPAMM.In multivariable model 1 both segment thickness , N = 7, MYH7 N = 4, TNNI3 N = 1). There was a trend to higher native T1 overtly hypertrophied segments  in genotype positive vs genotype negative patients, 1295.9 ± 65.1 vs 1272.3 ± 57.9 ms, P = 0.055. In the same segments there was no significant difference in ECV in genotype positive vs genotype negative patients, 37.1 ± 10.1 vs 34.8 ± 10.2%, P = 0.23).10/50 patients had presence of a genetic mutation known to cause HCM .Ecc-SPAMM is the best validated CMR method for the assessment of strain , 30. HowCellular changes that may be detected in HCM include altered calcium cycling, impaired biomechanical stress sensing and disturbed cardiac energy homeostasis  and extrThere is already clear evidence that in HCM both native T1 , 35 and The major shortcoming of native T1 is that it varies significantly between field strengths, scanner vendor and technique used to measure it  and in cWe have reported, from multivariable model 2, that native T1 but not LGE has a significant association with impairment of regional function. LGE, like ECV, is directly influenced by the extent of extracellular fibrosis with a strong linear correlation between the extent of LGE within a particular segment and the amount of collagen measured histologically .We identified that LGE, even after correction for segment thickness, had a significant association with Ecc-SPAMM (multivariable model 1) in keeping with previous studies which did not include T1 mapping , 7. HoweIn HCM, there is a strong correlation between extent of LGE and ECV expansion  althoughWe have also reported that segmental strain is strongly associated with segment thickness. These findings corroborate previous studies that have shown a relationship between degree of hypertrophy and presence of LGE and strain measured by speckle tracking echocardiography , 7 and fThe patients studied all had an established HCM with a diagnosis made according to current guidelines , 8. Our We have only measured strain from short axis measurements specifically because the strength of the segmental analysis that we have carried out is based on the fact that T1 maps, SSFP cines and LGE acquisitions can all be carried out in the identical short axis plane. Comparing strain from long axis cines to ECV from short axis maps would add an unacceptable degree of error.Regional strain impairment measured by feature tracking and SPAMM is predominantly associated with the degree of hypertrophy and native T1, but not extracellular fibrosis (LGE or ECV). These findings suggest that impairment of contractility in HCM may be mediated by mechanisms other than extracellular expansion that may include cellular changes in structure and function. The cellular mechanisms leading to increased native T1 and its prognostic significance remain to be established.


Pulmonary hypertension is associated with increased mortality and morbidity in the elderly population. Heart failure is a common cause of pulmonary hypertension. Yet, the relation between left heart parameters reflective of subclinical cardiac dysfunction and increased filling pressures, and pulmonary arterial pressures in the elderly population remains elusive. Within the population-based Rotterdam Study, 2592 unselected participants with a mean age of 72.6 years (61.4% women) had complete echocardiography data available. We studied the cross-sectional associations of left heart structure and systolic and diastolic function with echocardiographically measured pulmonary artery systolic pressure. Mean pulmonary artery systolic pressure was 25.4 mmHg. After multivariable-adjustment measures of both structure and function were independently associated with pulmonary artery systolic pressure: E/A ratio [0.63 mmHg (95% CI 0.35–0.91) per 1-SD increase], left atrial diameter [0.79 mmHg (0.50–1.09) per 1-SD increase], E/E′ ratio [1.27 mmHg (0.92–1.61) per 1-SD increase], left ventricular volume [0.62 mmHg (0.25–0.98) per 1-SD increase], fractional shortening [0.45 mmHg (0.17–0.74) per 1-SD increase], aortic root diameter [− 0.43 mmHg (− 0.72 to − 0.14) per 1-SD increase], mitral valve deceleration time [− 0.31 mmHg (− 0.57 to − 0.05) per 1-SD increase], and E′ [1.04 mmHg (0.66–1.42) per 1-SD increase]. Results did not materially differ when restricting the analyses to participants free of symptoms of shortness of breath. Structural and functional echocardiographic parameters of subclinical cardiac dysfunction and increased filling pressures are associated with pulmonary arterial pressures in the unselected general ageing population. Pulmonary hypertension can occur idiopathically or, most frequently, in association with a number of common clinical conditions, including heart failure and chronic obstructive pulmonary disease , 2. PulmHeart failure is a common cause of pulmonary hypertension. Underlying left ventricular failure represents the clinical phenotype on the extreme end of a continuum of left heart function. Yet, data on the relation between left heart parameters reflective of subclinical cardiac dysfunction and increased filling pressures, and pulmonary arterial pressures are scarce, especially in the elderly population at risk for heart failure , 5, 6. TThis study was conducted within the Rotterdam Study, an ongoing prospective population-based cohort study, started in 1990 in Rotterdam, the Netherlands. The rationale and design of the Rotterdam Study have been described in detail elsewhere , 8. In sAll 4423 participants who visited the research center during the fifth examination of RS-I 2009–2011), the third examination of RS-II (2011–2012) and the second examination of RS-III (2012) were eligible for this analysis. We excluded participants who did not undergo echocardiography (mostly due to logistic reasons), those with poor quality of echocardiography, and those in whom tricuspid valve regurgitation values were too small to measure, making it impossible to calculate echocardiographically measured pulmonary artery systolic pressure (ePASP). We also excluded participants without measurements of resting heart rate or body surface area, which were used as key co-variables. Our final analyses included 2592 participants , with a 2.5 MHz transducer. The protocol included 2-dimensional scanning in the parasternal long and short axis views, the apical and subcostal views. In addition, 2-dimension guided M-mode measurements of left ventricle and aortic root were obtained by scanning in the parasternal long axis view. Tissue Doppler imaging (TDI) was done in the apical 4-chamber view. All images were digitally stored and assessed offline by the echocardiographers.3 − LVEDD3)} + 0.6 )} + 0.6 . Left ve+ LVEDD) . Left ve+ LVEDD) .Pulsed wave Doppler in the apical 4-chamber view was used to measure the early transmitral ventricular diastolic filling velocity (E wave) and late diastolic filling velocity (A wave) during 3 cardiac cycles. TDI was used to measure the early diastolic longitudinal filling velocity of the septal mitral annulus (E′) during 3 cardiac cycles. The means of the E wave, A wave and E′ over the 3 cardiac cycles were calculated and used to calculate E/A ratio and E/E′ ratio. Mitral valve deceleration time was measured as the time between the peak E-top wave and the upper deceleration slope extrapolated to the zero baseline using a Continuous Wave Doppler.2 , LAD [0.79 mmHg (0.50–1.09) per 1-SD increase], E/E′ ratio [1.27 mmHg (0.92–1.61) per 1-SD increase], and LVvol [0.62 mmHg (0.25–0.98) per 1-SD increase], LVFS [0.45 mmHg (0.17–0.74) per 1-SD increase], AoD [− 0.43 mmHg (− 0.72 to − 0.14) per 1-SD increase], E′ [1.04 mmHg (0.66–1.42) per 1-SD increase], and mitral valve deceleration time [− 0.31 mmHg (− 0.57 to − 0.05) per 1-SD increase]. Table When restricting the analysis to the 1604 participants free of shortness of breath in the larger model, point estimates were similar to those obtained in the full study population. Table In our study among older community-dwelling adults, structural and functional left heart parameters reflective of subclinical cardiac dysfunction and increased filling pressures were associated with ePASP. Most of the associations persisted when we restricted the analysis to participants free of shortness of breath, implying that these associations are not driven by individuals with overt heart failure.Our findings corroborate with three recent other epidemiologic studies. The first included 6598 male recruits from the Israeli air force. The authors reported significant associations of, LAD, and LVEDD with ePASP . The thiWe hypothesized that left-sided echocardiographic parameters across the full spectrum would be associated with ePASP, as early alterations in left heart structure and function can herald increased filling pressures and manifest heart failure, which is a common cause of pulmonary hypertension. Remarkably, LVFS showed a change in the direction of effect after multivariable-adjustment. This warrants further research to elucidate the underlying mechanisms involved.Also, we observed that a greater AoD was associated with a lower ePASP. A similar association between AoD and ePASP was reported in the Israeli study . The Fra2), had a slightly worse left ventricular systolic function (mean LVFS 40%), and were more likely to report shortness of breath (47.5%). Thus, these participants were overall less healthy. Another 850 participants had undergone echocardiography, but had no tricuspid regurgitation or too small to quantify indicating they had a very low ePASP. These missing values will have affected the distribution of the studied echocardiographic parameters in our sample and resulted in an overestimation of the average ePASP, but are unlikely to have affected the β-estimates since we found no indications for nonlinearity in the data. Third, our population was older (mean age 72.6 years) and predominantly white (96.5%). Our results should therefore be extrapolated with caution to younger populations or those of other ethnic origins. Last, we did not have data available on more advanced or novel echocardiographic parameters, such as volumetric tracings, tissue Doppler-derived systolic function, and measures of strain.Some limitations of our study need to be addressed. First, right heart catheterization is the gold standard for pulmonary arterial pressure measurements, but due to its invasiveness, heart catheterization is not suitable for population-based studies. However, several studies have shown that ePASP correlates well with invasively measured pulmonary arterial pressure and that echocardiography is appropriate for measurement of PASP in this setting , 21. AlsOur work should be considered preclinical as this is the first study in the community-dwelling ageing population to demonstrate that parameters of subclinical left heart dysfunction and increased filling pressures correlate with subtle increases in pulmonary pressures. It remains to be studied whether progression to overt symptomatic pulmonary hypertension could be halted or controlled by pharmacological treatment in persons with subclinical left heart disease –26.Structural and functional echocardiographic parameters of subclinical cardiac dysfunction and increased filling pressures are associated with pulmonary arterial pressures in the unselected general ageing population.


The natural history is predominantly related to ventricular electric instability which may lead to arrhythmic SCD, mostly in young people and athletes2,3, but may progress with significant RV muscle disease and left-ventricular (LV) involvement and can result in right or biventricular heart failure4.Arrhythmogenic right ventricular dysplasia (ARVD) is an inheritable heart muscle disease that predominantly affects the right ventricle (RV) and predisposes to ventricular arrhythmias and sudden cardiac death (SCD)We report on a 54-year-old male with ARVD who underwent an epicardial ventricular tachycardia (VT) ablation using remote magnetic navigation (RMN) after functional imaging from a nuclear perfusion study was fused with a 3D segmentation from computed tomography (CT) imaging. A 54-year-old male patient was diagnosed in 2011 with ARVD by following the standard criteria for diagnosis including late gadolinium enhancement in cardiac magnetic resonance imaging (CMR)5 and fused with 3D segmentation from conventional contrast angiography CT raphy CT . Both seAfter obtaining written informed consent, the procedure was performed under deep-assisted sedation in the presence of an experienced cardiac anaesthetist with continuous invasive arterial blood pressure monitoring. An octapolar diagnostic catheter  was positioned in the RV, serving as the timing and pacing reference via the right femoral vein (8 Fr sheath). The magnetically-equipped ablation catheter  was introduced either via the epicardially positioned sheath  or via t6–8.Intracardiac electrograms were recorded on a recording system  and all electrogram and mapping information was displayed on the Odyssey platform . The magnetic navigation system  was used in conjunction with the cardio drive system. A detailed description of this system has been published previously9,10.Since the patient presented in SR at the beginning of the study, programmed stimulation was carried out in order to induce VT, which was hemodynamically not tolerated and required termination by overdrive pacing. Sequential electroanatomical mapping  was performed during SR to acquire a substrate map and identify late potentials. Subsequently, pace-mapping was performed  to identify exit sites for the various VTs . Multiple lesions at sites of best pacemap or at sites with late potentials .Final endpoint was the complete non-inducibility of any VT with up to 3 extras pacing from 2 different endocardial sites after the patient was completely awake. Hydrocortisone (10ml) was injected via the epicardial sheath, which was removed on the following day without evidence of epicardial effusionDuring a follow-up of more than 4 months, the patient has not experienced any further palpitations and no VT has been documented on his device via remote monitoring.1,13,14. Access to the pericardial space is nowadays a routine procedure and allows mapping of the epicardium, which presents in this patient cohort with significant substrate for re-entry tachycardia. Accessibility and mapping of the epicardial space is easily achieved using remote magnetic navigation. This has been demonstrated by several groups in various patient cohorts including ischemic and non-ischemic ventricular tachycardia8,15,16. The great advantage is that the operator is not exposed to scattered radiation and can manoeuvre the catheter without the risk of trauma around the ventricles  artefacts can make assessment of scar tissue by LGE particularly difficulttes ref. . This isRemote magnetic navigation allowed successful endo- and epicardial ablation of ventricular tachycardia in a patient with ARVD after failed conventional ablations. Functional image integration provided a substrate roadmap that allowed depiction of the epicardial scar and assisted in a very low radiation exposure.This project was supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.Sabine Ernst is a consultant to Biosense Webster and Stereotaxis, Inc.


Physical activity (PA) promotion in healthcare is an important strategy for increasing PA levels. Physiotherapists are well-positioned to promote PA, however no studies have investigated PA promotion by physiotherapists Australia-wide.An online survey of practicing Australian physiotherapists was conducted to investigate knowledge of the Australian Physical Activity and Sedentary Behaviour (PASB) guidelines and factors associated with increased promotion frequency. Participants were asked to state the PASB guidelines and a 4-component scoring system was used to measure knowledge. Multivariate logistic regression analysis was conducted to assess factors associated with frequency of promotion.257 Australian physiotherapists completed the survey. Only 10% were able to accurately state the PASB guidelines and 54% reported promoting PA to 10 or more patients per month. Males were nearly three times more likely than females to promote PA to 10 or more patients per month . Those who lacked counselling skills and felt PA promotion wouldn’t change their patients’ behaviour were much less likely to promote PA.Australian physiotherapists have poor knowledge of the Australian PASB guidelines and infrequently promote PA. Education and training in PA counselling and behaviour change strategies is indicated to enhance PA promotion by Australian physiotherapists. The World Confederation of Physical Therapists states that physiotherapists are ideally positioned to deliver physical activity (PA) promotion for both primary and secondary prevention of non-communicable diseases (NCDs) . They haPhysiotherapists around the world perceive that PA promotion is part of their role, with 50–99% of physiotherapists from Australia, Belgium, Brazil, Ireland and Nigeria agreeing this is part of their normal clinical work –11. A hiReported frequency of PA promotion amongst physiotherapists is fair, with 36–54% of physiotherapists in Australia and Nigeria promoting PA beyond therapeutic exercise to 10 or more patients per month , 8. StudOne strategy to increase the population’s PA levels is for health practitioners to incorporate PA promotion into routine healthcare . To enabA cross-sectional online survey was undertaken between January and March 2016. Using voluntary sampling, physiotherapists working in Australia were recruited through advertisements placed in physiotherapy-specific electronic publications and communications and via professional networks. Participants were included in the study if they self-reported they were currently practicing within Australia as a physiotherapist in any setting, including private practice, community health, public hospital or private hospital. To increase response rates, participants who completed the online questionnaire had an opportunity to win one of four AUS$100 sports vouchers.The online questionnaire was based on a previous questionnaire that had been used in physiotherapy and General Practice populations , 16. Minn = 27,370) [Sample size was based on the total number of registered physiotherapists in Australia in March 2015  . Using ap < 0.05 was used to determine which variables were retained. The model was assessed for goodness of fit using the Hosmer-Lemeshow chi-square test and an area under the receiver operator characteristic (ROC) curve. All quantitative analyses were conducted using the Statistical Package for Social Sciences (SPSS) version 22. Significance level was set at p < 0.05.Descriptive analyses were completed. Responses of physiotherapists who more frequently counselled patients to increase their PA levels (beyond therapeutic exercise) were compared to those who less frequently counselled patients to determine factors that are associated with greater frequency of PA promotion. This was achieved by dividing the total sample into two groups, ‘counselled <10 patients per month (less often)’ versus ‘counselled ≥10 patients per month (more often)’ , 10. AssA total of 257 Australian physiotherapists completed the survey Table . The majOnly one half of participants reported promoting PA beyond therapeutic exercise to 10 or more patients per month (Table Participants’ knowledge of the Australian public health messages varied Table . The majThe majority of participants agreed that PA promotion is part of the physiotherapist’s role and felt confident giving both general and specific PA advice to patients Table . OverallMale participants were almost 3 times more likely to promote PA beyond therapeutic exercise to 10 or more patients per month than females. If participants agreed that separate one-on-one consultations were a feasible option for promotion they were 3 times more likely to promote PA to 10 or more patients per month. Table Australian physiotherapists have poor knowledge of the Australian PASB guidelines. Yet, the majority of participants felt confident promoting PA and agreed that PA promotion is part of their role, with half the participants promoting PA beyond therapeutic exercise to 10 or more patients per month. To our knowledge, this study is the first to find an association between gender and frequency of PA promotion, with male physiotherapists nearly three times more likely than females to promote PA to 10 or more patients per month, regardless of the number of hours worked per week. This finding may have important practical implications, with nearly 70% of Australian physiotherapists being female . It is pFew studies have explored physiotherapists’ knowledge of the current PA guidelines. In 2010, Shirley et al. found that only one third of physiotherapists in NSW Australia were aware of the Australian PA guidelines. However, it was unclear if, and how, this study assessed the accuracy of participants’ responses when they were asked to describe the PA guidelines. In Ireland, 51% of physiotherapists were able to accurately recall the Irish PA guidelines . A recenIn addition to poor knowledge of the PA guidelines, participants’ knowledge of Australian public health messages relating to PA was limited. Only half of the participants agreed that generally being more active each day is enough PA to improve health. This may be due to physiotherapists believing that a larger amount of PA is needed for good health. This may also indicate that physiotherapists lack knowledge of the significant health benefits that can occur with small amounts of PA, such as half an hour of brisk walking on most days of the week . FurtherRegardless of the reasons why their knowledge was limited, our findings indicate that Australian physiotherapists require further education on all components of the Australian PASB guidelines, with a particular focus on resistance activities and sedentary behaviour. A systematic review of factors influencing health professionals PA promotion found that decreased PA awareness and knowledge results in decreased PA promotion . Thus, PIn our study, physiotherapists who lacked counselling skills, or felt that PA promotion wouldn’t change the patient’s behaviour and didn’t see one-on-one consultations as feasible options for PA promotion, were significantly less likely to promote PA. Previous studies have shown similar results , 24. To The findings for PA promotion role perception, barriers, feasibility and confidence are similar to other studies conducted with physiotherapists around the world , 7–11. ABarriers to PA promotion were few. ‘Other’ barriers, such as feeling it wouldn’t be appropriate with some patients, alongside lack of time, were the most frequently cited. While PA promotion may be inappropriate with some patients, such as those who are bed-bound or those with acute medical conditions, PA promotion can be adapted to be safe and appropriate for those with cognitive disorders and comorbidities –31. BrieLimitations to this study include a limited sample size and only offering the survey online, which may have limited responses from those that did not have access to an electronic device. Selection bias may have also occurred due to voluntary sampling, with the survey being promoted more widely in the area where the research team was located, and physiotherapists more interested in PA potentially more likely to complete the survey. There is also the potential for recall and social desirability bias. Physiotherapists may have over or under-estimated the number of patients they promoted PA to during the past month, and they may have inaccurately estimated their personal level of PA.Australian physiotherapists perceive PA promotion to be part of their role and feel confident promoting PA to their patients. Despite this, PA knowledge amongst Australian physiotherapists is poor. Training in brief PA counselling and behaviour change for practicing physiotherapists is indicated, particularly targeting female physiotherapists. If physiotherapists increase their PA knowledge, improve their PA counselling skills and take advantage of opportunities within routine physiotherapy consultations, they have the potential to increase PA levels of the Australian population.


Expansion of the myocardial extracellular volume (ECV) is a surrogate measure of focal/diffuse fibrosis and is an independent marker of prognosis in chronic heart disease. Changes in ECV may also occur after myocardial infarction, acutely because of oedema and in convalescence as part of ventricular remodelling. The objective of this study was to investigate changes in the pattern of distribution of regional  and global left ventricular (LV) ECV using semi-automated methods early and late after reperfused ST-elevation myocardial infarction (STEMI).Fifty patients underwent cardiovascular magnetic resonance (CMR) imaging acutely (24 h–72 h) and at convalescence (3 months). The CMR protocol included: cines, T2-weighted (T2 W) imaging, pre−/post-contrast T1-maps and LGE-imaging. Using T2 W and LGE imaging on acute scans, 16-segments of the LV were categorised as normal, oedema and infarct. 800 segments (16 per-patient) were analysed for changes in ECV and wall thickening (WT).P < 0.001). Normal segments which demonstrated deterioration in wall thickening at follow-up showed significantly increased Δ ECV compared with normal segments with preserved wall thickening at follow up .From the acute studies, 325 (40.6%) segments were classified as normal, 246 (30.8%) segments as oedema and 229 (28.6%) segments as infarct. Segmental change in ECV between acute and follow-up studies (Δ ECV) was significantly different for normal, oedema and infarct segments  contains supplementary material, which is available to authorized users. Following ST-elevation myocardial infarction (STEMI), even with immediate mechanical reperfusion therapy, 24–30% patients develop adverse left ventricular (LV) remodelling , 2. LV rThe chronic phase of LV remodelling involves compensatory myocyte hypertrophy and alterations in ventricular geometry to distribute the increased wall stresses more evenly . Early pCardiovascular magnetic resonance (CMR) offers comprehensive multi-parametric structural and functional assessment in patients with STEMI . Using eThis study aimed to investigate whether ECV expansion of normal myocardium occurs after STEMI and whether it is associated with a reduction in contractile function between baseline and follow up assessment. We also sought to determine the baseline CMR parameters that are most strongly associated with segmental functional change at follow up.Patients with acute STEMI were prospectively enrolled from a single UK tertiary centre. The study design is detailed in Fig. The inclusion criteria were as follows: patients with first time acute STEMI treated by primary percutaneous coronary intervention (PPCI) within 12-h of onset of chest pain. Acute STEMI was defined as per current international guidelines . ExclusiCoronary angiography and revascularisation were performed in a standard fashion as per current best practice guidelines , 16. TIMAll patients underwent CMR imaging at either 1.5 Tesla  or 3.0 Tesla . The choice of field strength was arbitrary and was predominantly dictated by availability of the scanners. A dedicated cardiac phased array receiver coil was used . Acute CMR imaging was scheduled within 72-h of the index presentation and patients were invited to attend for a further CMR study at 3-months follow-up. The same field strength scanners were used for respective patients as for the acute scans.Cine, T2 W-imaging, EGE and LGE imaging were performed in contiguous stacks of short-axis slices covering the entire LV for each acquisition. The same slice geometry, position and 10 mm slice thickness were used for all pulse sequences.Native and post-contrast T1-maps were planned using the ‘3-of-5’ approach . Post-coFor each pulse sequence, images with artefact were repeated until any artefact was removed or minimized. The highest quality images were used for analysis. Cine, T2 W-images, EGE-images and LGE-images were evaluated offline using MASS research software .Basic CMR image analysis, T1-maps quality assurance checks, pulse sequence parameters and imaging protocol are described in the online Additional file Sixteen segments of the LV excluding the apex, adapted from the 17 segments of the American Heart Association (AHA) model , were viSegmental myocardial systolic wall thickening (WT) analysis was performed for each slice based on endo- and epi-cardial contours. For each segment, end-diastolic and end-systolic wall thickness  were recorded as per previously published literature . This meglobal ECV)*(indexed LVEDV) [ECV maps were generated for the 3 slices  from pre−/post-contrast T1-maps and haematocrit as per the standard techniques . The endd LVEDV) . For eacAdverse LV remodelling was defined as an absolute increase of LV end-systolic volumes >15% at 3 months follow-up , 25.For intra−/inter-observer assessments, 48 segments were selected from three randomly chosen scans. To test the inter-observer reliability of segmental ECV values, two blinded observers carried out independent segmentation of ECV-maps (PG and SC) in these segments. To test intra-observer reliability, one observer (PG) undertook a second blinded analysis after three months.p < 0.1). Intra−/inter-observer agreement was assessed by investigating the coefficient of variability (CV), concordance correlation coefficient (CCC), precision and accuracy. All statistical tests were 2-tailed; p values <0.05 were considered significant.Statistical analysis was performed using SPSS® Statistics 21.0 . Normality of quantitative data was established using the Shapiro-Wilk test. Normally distributed continuous variables are expressed as mean ± SD and non-normally distributed are expressed as median (25th–75th quartile ranges). Demographic comparisons between patients with rise and fall of ECV at follow-up, in the normal myocardial segments, were performed with an independent samples t-test for normally distributed variables and by Mann-Whitney independent t-test for not normally distributed. For paired comparison in Table n = 8) versus 0.9 ± 0.9%  [We used data of remote zone ECV from published literature using to inform the sample size calculations for this study. In a previous study, delta remote zone ECV in patients with/without adverse LV remodelling were: 0.9 ± 2.2%  . Using t n = 32) . PresumiSeventy patients were considered for inclusion, of which 50 had baseline and follow-up CMR Fig. . Acute sP = 0.05). There were no differences relating to the field strength of the scanner that was use and the 3 T patients, 10 patients (55.6%) demonstrated ECV expansion in normal myocardial versus 18 (56.2%) on the 1.5 T (P = 0.96 for comparison of 3 T and 1.5 T). LV mass reduced significantly from baseline to follow-up, but global ECV and myocyte cell volume showed no significant change  segments were classified as normal, 246 (30.8%) segments were classified as oedema and 229 (28.6%) segments were classified as infarct segments. Myocardial oedema was only seen in the peri-infarct zone of the culprit vessel.For the 48 segments which were analysed, intra-observer CV was 6%, with excellent CCC , high precision (0.95) and accuracy (0.99). For the inter-observer analysis, CV was 7%, with good CCC  and high precision (0.93) and accuracy (0.99).P = 0.03).Oedema and infarct segments demonstrated significant reductions in ECV at follow-up Table . ConversP < 0.001)  and to follow-up segmental WT (P < 0.0001) .Acute segmental ECV demonstrated significant correlation to both acute segmental WT (1) Table . There w1) Table , Fig. 4.‘Supplementary material’. Acute ECV of the normal, oedema and infarct segments demonstrated an inverse relation to final follow-up radial strain .By univariable analysis of all demographic and CMR parameters, acute oedema and infarct segment ECVs demonstrated association to number of segments (per-patient) that had improvement in function Table . On multP = 0.04)  Table . InfarctThe present study demonstrates that 1) in reperfused STEMI, normal myocardial segments show a subtle expansion of the ECV between baseline and 3 month follow-up; 2) conversely, oedematous and infarcted segments show a significant reduction in ECV at follow up; 3) normal segments that demonstrate deterioration in segmental function at follow-up show a substantial increase in delta-ECV from baseline to follow up; 4) acute infarct ECV demonstrates the best association with the number of segments with functional recovery . We speculate that in triple vessel disease, coronary steal may reduce flow in non-culprit vessels due to better flow down the revascularised culprit vessel, which may cause adverse tissue level remodelling [Previous studies have already shown that ECV is raised in ‘remote’ myocardium in acute STEMI , 28. Remodelling –31. Otheodelling .Associations of segmental ECV and segmental and global function have been studied previously , 32, 33.Remote  myocardial dysfunction after STEMI is considered the main reason why some patients demonstrate function loss that is disproportionate to infarct size , 34. BogA recent study from our group demonstrated that acute ‘infarct zone’ ECV is predictive of regional and global LV functional recovery, and adds prognostic value over LGE . ParticuThis is the first in-vivo study that reports longitudinal changes in segmental ECV in non-infarcted normal, oedema and infarcted LV segments. Our data suggest that non-oedematous, non-infarcted normal LV myocardium undergoes remodelling with a subtle expansion of the extracellular matrix Fig. . In partOf 70 patients that underwent initial screening for recruitment only 50 patients underwent the entire protocol possibly introducing an element of selection bias. However, in a clinical study of acutely ill patients, exclusion or drop out of patients is common and our exclusion rate is within that reported in similar previous reports , 37. TheThis study suggests that following reperfused STEMI, the ‘normal’ LV myocardium undergoes remodelling with a subtle expansion of the extracellular matrix. In particular, normal segments which have functional loss demonstrate significant expansion of the extracellular space. Additionally, acute myocardial ECV of normal segments was significantly higher in patients who experienced adverse LV remodelling. Myocardial segments with oedema and infarction demonstrate significant reduction in ECV.


AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients  with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction‐relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/μm2 were 14.7% higher in mitochondria than the rest of the cytoplasm (P < 0.001). There were no significant sex or diagnostic group differences in CML counts  and no significant correlations between CML counts and age, HgbA1c or myofilament function indexes. However, left atrial volume was significantly correlated with CML counts . We conclude that in CBG patients CML is abundant within cardiomyocytes but minimally associated with collagen, suggesting that AGEs do not directly modify the stiffness of myocardial collagen. Coexistent HTN or HTN + DM do not significantly influence CML abundance. The correlation of CML counts with LAV suggests an influence on diastolic function independent of HTN, DM or sex whose mechanism remains to be determined.Advanced glycation end‐products ( Advanced glycation end‐products (AGEs) result from adduction of glucose to proteins with subsequent modification by a series of nonenzymatic oxidation‐reduction reactions  is a ubiquitous AGE linked to various complications of DM  method to detect CML in myocardium using a specific antibody  divided into three groups: (1) controls without HTN or DM; (2) HTN; and (3) HTN+DM. We related CML measurements to clinical and demographic variables, echocardiographic measures of LV structure‐function, contraction‐relaxation properties of demembranated (skinned) strips obtained from the biopsies, and a panel of proinflammatory/profibrotic plasma biomarkers. We also measured myocardial CML in a group of brain‐dead organ donors without known heart or coronary artery disease (CAD). Finally, in a small subset we used the IEM method to examine pentosidine, an AGE that undergoes extensive cross‐linking  University of Vermont Medical Center (UVMMC), Burlington, Vermont, the clinical facility of the UVM College of Medicine (UVMCOM); (2) the Ralph H. Johnson VAMC and Medical University of South Carolina Hospital Authority, Charleston, South Carolina (referred to collectively as MUSC); and (3) selected NHLBI Heart Failure Research Network (HFN) Centers  between October 1, 2008 and August 6, 2012. All patients signed consent forms approved by their respective IRBs. Most of these patients also were enrolled in a previously published report on passive myocardial stiffness in HFpEF  age > 21 years; (2) LVEF > 0.50; (3) normal anterior and lateral wall motion during preoperative assessment by echocardiography or LV cineangiography .Patients were excluded for the following reasons: (1) Previous transmural myocardial infarction; (2) significant valvular or non‐coronary heart disease; (3) chronic pulmonary disease requiring oxygen therapy; (4) non‐ cardiac diseases or conditions that can affect myocardial function; (5) anemia (Hgb < 13.0 g/dl); (6) serum creatinine > 2.0 mg/dL; (7) off‐pump or emergency CBG; (8) active malignancy, infection, connective tissue disease, severe liver disease; (9) inability to provide informed consent.and they were receiving medications to lower their blood pressure. DM was diagnosed if documented in the medical records. Patients were classified as controls if they had neither HTN nor DM.HTN was diagnosed if patients had been told of the diagnosis and/or it was documented in their medical records Demographic, historical and laboratory data, medications and coronary anatomy were recorded. CAD severity was graded based on number of major vessels  with a stenosis >70%, with left main coronary artery considered as two vessels.3 specimens were dissected from epicardial, midwall, and endocardial layers and underwent CML analysis.Hearts from brain‐dead organ donor subjects were made available through the Gift of Life Donor Program . Patients thought to have died of cardiac disease or to have CAD in life were excluded. After in situ cardioplegia, hearts were explanted and transported on ice to the laboratory of K.B.M. at the University of Pennsylvania. Full thickness biopsies of the anterior LV were obtained from 6 hearts from eligible patients. ~ 1 mmEchocardiograms obtained at UVMMC and MUSC were interpreted in blinded fashion at MUSC by MZ using standard criteria  was calculated as force per cross‐sectional area. TMAX was taken at pCa 4.5. T minus relaxed tension at pCa 8 (TpCa8) at each pCa was normalized to maximum developed tension (TMAX–TpCa8). These data were used to estimate pCa50. Passive tension was taken as TpCa8.These methods have been described previously , and soluble ST2 (sST2)] were measured as well as NT‐proBNP)  −1,−2, −3, −7, −8 and −9 and tissue inhibitors (TIMPs) −1, −2, −3, and −4], and a proinflammatory/profibrotic state .ACEIs/ARBs, statins and hypoglycemic agents are reported to reduce AGE accumulation  had CML counts in the same range as CBG patients. There were no obvious differences in epicardial, midwall and endocardial CML counts and, as in CBG patients, counts were higher in mitochondria than the rest of the cytoplasm  and LA volume (P = 0.002). Individual testing revealed a higher RWT in HTN (P = 0.03) and HTN+DM (P = 0.003) versus controls. LA volume was significantly greater in HTN versus controls (P = 0.001), with a trend toward a higher value in HTN+DM (P = 0.052). There was also a trend toward a difference (P = 0.06) between diagnostic groups for E/E', with higher values in HTN and HTN+DM. The only significant correlations with CML counts were LA volume in the HTN group  and LA volume for the entire cohort .Echocardiographic‐Doppler data are shown in Table MAX (P = 0.024). Individual testing revealed a higher value in controls (19.0 ± 1.1 mN·mm−2) versus HTN  but not HTN+DM . There were no group differences in pCa50 or TpCa8 and no significant correlations with CML counts in any group or the entire cohort.There was a significant diagnostic group difference for TP < 0.001), CRP (P = 0.006), and ST2 (P = 0.002) (Table P = 0.008) and HTN+DM (P < 0.001) versus controls. For CRP, HTN was greater than controls (P = 0.001). ST2 was significantly greater in HTN (P < 0.001) and HTN+DM (P = 0.006) versus controls. There was a trend toward a difference for NT pro‐BNP by diagnostic group (P = 0.084), with higher values in HTN and HTN + DM compared with controls. No other biomarkers achieved statistical significance for group differences . The only significant CML‐biomarker correlation was with TIMP1 in controls .There were significant group differences in TIMP1 (2) Table . By indiUsing an electron microscopic method that provides much greater resolution than light microscopy  and a homologue, LOX‐like 2 . E/E' was also nearly significantly greater in HTN and HTN + DM (ANOVA P = 0.06). Taken together, these results are consistent with diastolic dysfunction in association with concentric remodeling in HTN and HTN + DM. CML counts were positively correlated with LA volume in HTN patients and in the entire cohort, suggesting a direct relationship between CML and diastolic dysfunction. This correlation was highly significant. Moreover, LA volume is a relatively robust index of diastolic function as it is less load sensitive than Doppler‐derived indexes.Echocardiography revealed increased RWT in HTN and HTN + DM, indicating concentric remodeling. LA volume was larger in HTN versus controls and nearly so in HTN + DM . This suggests that the diastolic dysfunction we observed in HTN and HTN+DM patients does not have a myofilament basis. The limited amount of tissue available precluded analysis of other myocardial properties that influence diastolic function, for example, ion transport. Additionally, the relatively higher abundance of CML in mitochondria suggests the possibility of diastolic dysfunction caused by depressed energy‐dependent processes such as Ca2+ re‐uptake by the sarcoplasmic reticulum.There were no correlations between CML and myofilament function, including pCaBiomarker correlations with CML counts were very modest. It is unclear why these were not more evident. Perhaps we did not select optimal biomarkers. However, we did observe diagnostic group biomarker differences and the biomarkers we chose are generally considered to provide good screening for alterations in inflammation and collagen homeostasis.HFN sites recruited patients who are relatively scarce amongst the CBG population. This allowed us to quantify CML in larger numbers of females and controls. However, research echocardiograms and biomarkers were not obtained and myofilament studies could not be uniformly performed in these patients. Moreover, 98 patients is a relatively modest size cohort and relatively small group differences and/or correlations between CML counts and echocardiographic data, biomarkers and myofilament results could have been missed.All of our CBG patient biopsies were obtained from the epicardial layer of the LV. Therefore, it is possible that transmural variations in CML or pentodisine abundance in cardiomyocytes and/or the ECM could have been missed. However, this seems somewhat unlikely since there were no obvious transmural CML differences in the donor hearts, including those with cytoplasmic CML counts similar to the CBG patients.Another limitation is the possibility that some control patients had unrecognized hypertension, a common problem. However, we believe this is unlikely since all of the control patients had seen physicians at various times before CBG and had not been told of hypertension, none had elevated blood pressures during hospitalizations or clinic visits before CBG and none had received drugs to treat hypertension. Finally, we did not assess RAGE abundance in the biopsies. RAGE is a vascular endothelial receptor and it is in the nature of our biopsies that we do not consistently image small blood vessels. Had we been able to do so, this might have provided valuable additional information about the role of AGEs, for example as a cause of increased collagen content.CML is readily detectable within cardiomyocytes from CBG patients. Abundance is somewhat greater in mitochondria and not significantly influenced by sex or HTN with or without coexistent DM. Localization of CML and pentosidine in association with collagen is very limited. Taken together, our results do not support AGEs as an important mechanism of collagen cross‐linking and increased passive stiffness or of altered myofilament function in human myocardium. However, the highly significant correlation of cytoplasmic CML counts with LA volume suggests an as yet undefined role in diastolic dysfunction.None declared.


Our review of real-time three-dimensional echocardiography (RT3DE) discusses the diagnostic utility of RT3DE and provides a comparison with two-dimensional echocardiography (2DE) in clinical cardiology. A Pubmed literature search on RT3DE was performed using the following key words: transthoracic, two-dimensional, three-dimensional, real-time, and left ventricular (LV) function. Articles included perspective clinical studies and meta-analyses in the English language, and focused on the role of RT3DE in human subjects. Application of RT3DE includes analysis of the pericardium, right ventricular (RV) and LV cavities, wall motion, valvular disease, great vessels, congenital anomalies, and traumatic injury, such as myocardial contusion. RT3DE, through a transthoracic echocardiography (TTE), allows for increasingly accurate volume and valve motion assessment, estimated LV ejection fraction, and volume measurements. Chamber motion and LV mass approximation have been more accurately evaluated by RT3DE by improved inclusion of the third dimension and quantification of volumetric movement. Moreover, RT3DE was shown to have no statistical significance when comparing the ejection fractions of RT3DE to cardiac magnetic resonance (CMR). Analysis of RT3DE data sets of the LV endocardial exterior allows for the volume to be directly quantified for specific phases of the cardiac cycle, ranging from end systole to end diastole, eliminating error from wall motion abnormalities and asymmetrical left ventricles. RT3DE through TTE measures cardiac function with superior diagnostic accuracy in predicting LV mass, systolic function, along with LV and RV volume when compared with 2DE with comparable results to CMR. In this article, we review current literature regarding the evaluation of RT3DE through a transthoracic echocardiography approach for characterization of cardiac anatomy and function for clinical decision-making.The newly developed real-time three-dimensional echocardiography (RT3DE) imaging technique aims to noninvasively characterize cardiac anatomy and function for clinical decision-making. This novel technique uses temporal information, along with spatial feature extraction, to compile information of cardiac anatomy and function.5 End diastolic volume, the largest cavity volume in the cardiac cycle, has remained the selected frame for measuring the LV capacity volume and LV epicardial volume. Using the long axis of the LV cavity from apex to base as the selected reference, additional points on each side of the endocardial surface along a 45° rotated axis are selected and combined to form the complete surface of the LV cavity. A partial differential equation is then used to create a 3D surface detection algorithm and direct the surface toward the necessary endocardial position. Next, the end diastolic volume of the surface can be measured to obtain LV cavity volume and LV epicardial volume. Subtracting the LV cavity volume from the LV epicardial volume provides the LV myocardial volume, which is then multiplied by myocardial density to provide LV mass.6 Compared with 2DE and cardiac magnetic resonance (CMR) imaging, RT3DE provides the most accurate approximation of the LV mass.6RT3DE has been used in the literature to collect 3D scan volume of the LV cavity.5 Steady pacing minimizes the spatial and temporal resolution limitation with one beat analysis in 2DE.7 In the literature, the attainability of one beat full volume of LV has been noted to be ∼84%.8 Currently, there exist data collection systems that utilize sampled matrix array transducers capable of acquiring volumetric data by 3D analysis of multiplanar measurements of volumes.7 A study conducted by Corsi et al. illustrates multiple LV volume time curves depicting its accuracy in volumetric analysis.9 Comparing these curves with CMR data of the same patients revealed a high degree of correspondence of r = 0.98 and that were thus determined to be statistically similar. Comparing the LV function of nine dilated cardiomyopathy patients with that of nine control patients further validated this novel imaging modality. The RT3DE results showed that the cardiomyopathy patients had significantly lower LV function than the control with no statistical significant difference between RT3DE and CMR.10The RT3DE is useful in analyzing the LV volumes, ejection fraction, systolic function, and dyssynchrony.10 Some investigators, such as Sugeng et al., have compared RT3DE with the cardiac CT technique to estimate the ejection fraction.10 Moreover, RT3DE was shown to have no statistical significance when comparing the ejection fractions. The measured regional ejection fraction from RT3DE was also found to be in concordance with those from CMR, with zero statistical bias. This indicates a high level of agreement between RT3DE data and CMR data as a reliable source of LV (volume) function.The American Heart Association has referred to the ejection fraction as a measure of blood pumping from the LV with each contraction.11 Specifically, in RV stroke volume determination, proper evaluation has been hindered because of its innate features, such as its infundibulum, asymmetrical shape, and trabecular character.11 Because of the significant structural difference between both ventricles, listed hereunder are the recommended approaches in determining the respective stroke volumes using RT3DE.Errors in the LV volume have been shown to contribute to inaccurate volume estimations when the following deformities are present: wall motion abnormalities, aneurysms, and disproportionate LV and RV cardiac chambers.12 Moreover, RT3DE data collection allows for direct quantification of the LV stroke volume. It remains unaffected by foreshortened LV views and unreliant geometric modeling estimations. Thus, error from wall motion abnormalities and asymmetrical left ventricles is eliminated.12–18A common approach used in LV stroke volume determination is the analysis of RT3DE data sets gathered by semiautomated recognition software of the LV endocardial exterior. This allows for the volume calculation within the LV for specific phases of the cardiac cycle, ranging from end systole to end diastole.20 The use of the disk summation technique proved to be an accurate methodology for RV volume determination. The disk summation technique is an in-depth analysis of disk thickness, orientation, and gain setting in the right ventricle.20 A summation of numerous disks are made that layer the RV endocardial surface to measure the ventricle volume change during the cardiac cycles of end diastole and end systole. With the data sets obtained from RT3DE data sets, the base area of each disk and the vertical axis chamber height are summed to determine RV stroke volume. Of note, ventricular papillary muscle and the cardiac trabeculations are not included in the summation, producing a slight volume overestimation.21The RV stroke volume determination has proven to be a significant challenge because of its complex chamber geometry. Initially, a lack of RT3DE observation of the RV by the conventional ventricular analysis method resulted in inaccurate estimations.23 The improved reproducibility and accuracy of the LV volume and ejection fraction measurements lend precision during cardiac evaluation.11 In contrast, 2DE produces planar images with inaccuracies, because of microembolization of image capture from beat to beat by the heart, less experienced in RT3DE. One can evaluate regional wall motion in the entire heart, which can be used in the determination of abnormal wall motion with minimal artifacts.24 Unfortunately, RT3DE, like 2DE, has limitations and potential error.RT3DE provides incremental value for the assessment of intracardiac masses through offering a more precise evaluation of the shape, size, and the mass composition.25 Interestingly, the volume estimation by RT3DE was similar to the CMR images, but lower at institutions with lower level of experience.25 The RT3DE inconsistent estimation of the ventricular volumes was because of sonographer's inability to recognize the difference between myocardium and trabeculae tissue.27 Tracing the endocardium so that it includes trabeculae was a solution suggested to minimize inconsistent estimation of ventricular volume by RT3DE.Other potential sources of error described in the literature include phantom imaging, intermodality analysis-related differences, and differences in LV boundary identification, such as inclusion of endocardial trabeculae and mitral valve plane.29 specifically, the low rates of frames caused by imperfect translation of data sets and lack of agreement among the various softwares used for 3D evaluation.30–33 Overall, the RT3DE method has improved image quality from the standard 2D images and measured cardiac function with superior diagnostic accuracy in predicting LV mass, systolic function, along with LV and RV volume when compared with 2DE. The results from the regional wall motion abnormalities need to be verified in larger studies.The apparent limitations of the RT3DE are largely related to its ongoing development,


Amiodarone is effective in suppressing arrhythmias in heart failure patients. We investigated the effect of long-term amiodarone administration on myocardial fibrosis and left ventricular (LV) remodeling in a porcine model of ischemic cardiomyopathy. Eighteen infarcted farm pigs were randomized to receive long-term amiodarone administration for 3 months (n = 9) or conventional follow-up (n = 9). Evolution of LV remodeling over 3 months post-myocardial infarction was examined at tissue level , organ level (LV structure and function assessed by echocardiography), and systemic level (BNP and MMP-9 levels). Long-term administration of the standard anti-arrhythmic doses of amiodarone was not associated with adverse effects on myocardial fibrosis and other features of adverse cardiac remodeling. This favorable safety profile suggests that long-term anti-arrhythmic therapy with amiodarone warrants further clinical investigation in the subpopulation of heart failure patients with significantly increased burden of arrhythmias. Left ventricular (LV) remodeling is a complex pathophysiologic process characterized by changes at molecular, cellular and tissue level  with a tidal volume of 10–15 ml/kg of body weight and a respiratory frequency of 15/min. Throughout the experiment animals received intravenous infusion of propofol 10 mg/kg/h, fentanyl 20 g/kg and cisatracurium 0.2 mg/kg/20 min. The heart was accessed by lateral thoracotomy and myocardial biopsies were procured from the base of the LV. Afterwards, animals underwent induction of acute myocardial infarction (AMI) by permanent ligation of the left anterior descending coronary artery distal to the 1st diagonal branch, followed by closure of the chest. Animals were randomized into two groups: (a) animals in Group 1 (n = 9) received a loading dose of amiodarone (20 mg/kg IV during AMI) followed by daily p.o. administration of amiodarone ; (b) animals in Group 2  underwent conventional follow-up. Animals were followed for 3 months. One month post-MI animals underwent transthoracic contrast echocardiography and collection of blood samples. Three months post-MI, animals underwent transthoracic contrast echocardiography, collection of blood samples and procurement of myocardial biopsies from the base of the LV and heart explantation. The explanted heart was sectioned into 1-cm-thick short-axis slices. Each slice was photographed with a digital camera, and infarct size was determined as the percentage of LV by manual tracing by a researcher blinded to treatment allocation.Animals were pre-anesthetized by intramuscular administration of ketamine (15–20 mg/kg), midazolam (0.5 mg/kg) and atropine (0.05 mg/kg). Auricular vein catheter placement was followed by induction of anesthesia with propofol (2 mg/kg). After induction of anesthesia, animals underwent transthoracic contrast echocardiography  and collection of blood samples. This was followed by endotracheal intubation and mechanical ventilation. All animals received mixtures of atmospheric air and oxygen . Immunohistochemistry experiments were performed using a peroxidase-conjugated streptavidin–biotin system and diaminobenzidine as a substrate. To achieve a high degree of reproducibility we avoided manual staining. Histochemical stains were performed using the automatic Artisan Special Stains System  and the immunohistochemistry experiments were performed on the Autostainer .Advanced digital microscopy allowed examination of the entire heart tissue areas from the epicardium to the endocardium Fig. , as descWe set the staining color threshold of the ImageScope 10.0 colocalization analysis algorithm to accurately identify collagen on the basis of its blue color as previously described  were accepted for size measurement if they met the following criteria: (a) cellular cross-sections present (b) visible and round shaped nuclei located close to the cell center and (c) intact cellular basement membranes, as described previously  died during induction of AMI due to arrhythmia. One animal (randomized to the amiodarone group) died 1 week post-MI , and one (randomized to the amiodarone group) due to pulmonary edema. Five animals in each group completed the 3-month follow-up and were included in the analysis.Absolute values of echocardiography-measured parameters are provided in Table Macroscopic histological assessment of infarcted tissue did not reveal any morphometric differences between the two groups; infarct size  and infarct circumference  were similar between groups. Microscopic histological assessments of cardiomyocyte size, vascular density and myocardial fibrosis are provided in Table The levels of circulating BNP and MMP9 were measured as biochemical markers of adverse cardiac remodeling , organ (LV structure and function) and systemic level (levels of circulating BNP and MMP-9). While LV dilatation (as assessed by echocardiographic measurement of LVEDD) was attenuated in animals receiving amiodarone, this was not accompanied by concomitant beneficial changes in histological and biochemical indices of remodeling. In addition, since amiodarone is known to exert anti-beta adrenergic effects (Polster and Broekhuysen Long-term experimental oral administration of amiodarone in doses similar to the ones used in the clinical setting was not associated with adverse effects on myocardial fibrosis and other features of adverse cardiac remodeling. Given the promising results of amiodarone effectiveness in suppressing cardiac arrhythmias, these new safety findings suggest that anti-arrhythmic therapy with amiodarone warrants further clinical investigation in the subpopulation of heart failure patients with increased burden of supraventricular or life-threatening ventricular arrhythmias.


The vast majority  of thalassemia patients at risk of iron overload live in countries with limited red cell transfusions and chelating agents, with serum ferritin used as the method for iron monitoring. Cardiac iron can cause heart failure, but iron detection using CMR is perceived as expensive, time consuming and difficult. Parametric mapping (T2* or T1) can be fast and allows instant recognition of iron loading.We aimed to perform CMR in the developing world to quantify cardiac and liver iron, assessing its speed, cost, reliability, and clinical information yield.In a leading government hospital in Bangkok, Thailand we set up an ultrafast mapping protocol and analysis pipeline. In 2 days, 128 scans were performed in 97 thalassaemia patients and 11 healthy volunteers. The protocol consisted of: localisers, HASTE, pilots, T2* and T1 maps figure , and 2 aBaseline patient characteristics are shown in table Ultrafast CMR in the developing world using parametric mapping for iron overload is possible. We have demonstrated that 60 scans a day at 8 minutes per scan is achieveable. A follow-up study and pilot clinical service is underway.