Radiofrequency catheter ablation of atrial fibrillation (AF) has been proved to be effective and to prevent progressive left atrial (LA) remodeling. Cryoballoon catheter ablation (CCA), using a different energy source, was developed to simplify the ablation procedure. Our hypothesis was that successful CCA can also prevent progressive LA remodeling.sept, Aalat), LA filling fraction (LAFF), LA emptying fraction (LAEF) and the systolic fraction of pulmonary venous flow (PVSF). Detailed left ventricular diastolic function assessment was also performed.36 patients selected for their first CCA because of nonvalvular paroxysmal AF had echocardiography before and 3, 6 and 12 months after CCA. LA diameters, volumes (LAV) and LA volume index (LAVI) were evaluated. LA function was assessed by: early diastolic velocities of the mitral annulus (Aap < 0.05), maximal LAV , LAVI  and the maximal LA longitudinal diameter  had all increased. PVSF  and LAFF  had decreased. In contrast, after successful cryoballoon ablation LA size had not increased and LA function had not declined. In the recurrent group LAEF was significantly lower at baseline and at follow-up visits.Excluding recurrences in the first 3-month blanking period, the clinical success rate was 64%. During one-year of follow-up, recurrent atrial arrhythmia was found in 21 patients (58%). In the recurrent group at 12 months after ablation, minimal LAV (38 ± 19 to 44 ± 20 ml; In patients whose paroxysmal atrial fibrillation recurred within one year after cryoballoon catheter ablation left atrial size had increased and left atrial function had declined. In contrast, successful cryoballoon catheter ablation prevented progressive left atrial remodeling. The relationship between left atrial (LA) dilatation and atrial fibrillation (AF) has been widely accepted for a long time . ElectroRadiofrequency catheter ablation (RFCA) can affect left atrial size and function either from the scar caused by the ablation or from reverse atrial remodeling following conversion to normal sinus rhythm. After successful RFCA of atrial fibrillation, LA size has been found to decrease and LA function and left ventricular diastolic function to improve; the process has been called 'reverse LA remodeling'. In contrast, after an unsuccessful catheter ablation, opposite changes were observed -13 and cCryothermal energy is an alternative energy source that has been developed to overcome some of the disadvantages of RFCA. Cryoenergy offers increased catheter stability, less endothelial disruption with lower thromboembolic risk, and minimal tissue contraction with healing, less generation of inhomogeneous lesions, less oesophageal damage and fewer pulmonary vein stenoses. Balloon-based cryo-technology potentially offers a simpler and faster means of isolating the pulmonary veins that, theoretically, relies less on the dexterity of the operator and causes less scar in the left atrium. Previous studies suggest this is a safe and feasible approach with a similar success rate in patients with paroxysmal AF (PAF) to radiofrequency catheter ablation .Left atrial remodeling has not been examined in the previous studies which used cryoballoon catheter ablation of patients with AF ,16. Our 36 consecutive patients with recurrent, symptomatic, nonvalvular PAF were enrolled in the study between June 2008 and July 2009. All had failed to respond antiarrhythmic  or beta blocker therapy. They underwent their first catheter ablation by the cryoballoon technique.The study was carried out in compliance with the Helsinki Declaration and was approved by the Regional and Institutional Scientific and Research Ethics Committee of the Semmelweis University Budapest (reference number: TUKEB 70/2008). All patients gave written informed consent before participating in the study.As described in our previous report , all patAntiarrhythmic drugs were stopped 5 half-lives before the ablation, and were not continued afterwards. Oral anticoagulation was before and after ablation, according to the CHADS2-score based on the valid guideline .Comprehensive transthoracic echocardiographic examinations were performed in all patients during sinus rhythm before, and 3, 6 and 12 months after cryoballoon catheter ablation. Transoesophageal echocardiography was performed in all patients before catheter ablation, to exclude left atrial and left atrial appendage thrombus. Transthoracic and transoesophageal echocardiography were performed within 24 hours of each other.After the ablation, follow-up examinations at 1, 3, 6 and 12 months included clinical history and examination, ECG and 24-hour Holter ECG. A 10-day transtelephonic ECG was performed before the 3-month, 6-month and 12-month follow-up visits.Based on the definition of the Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation , cryobalIn order to evaluate the effect of all episodes of recurrent arrhythmia, recurrences in the blanking period were also taken into account for the final analysis. So the patients were divided into recurrent and arrhythmia-free (AF-free) groups. The recurrent group was defined as patients with recurrent atrial arrhythmia at any time during the follow-up.Transthoracic echocardiography was performed with a General Electric Vivid S6 machine .sept, Salat) using pulsed-wave tissue Doppler echocardiography (TDE).Left ventricular (LV) global systolic function was assessed by ejection fraction (EF) evaluated by the modified biplane Simpson's rule. LV longitudinal systolic function was assessed by septal and lateral systolic velocities of the mitral annulus (Samax) was obtained at left ventricular end-systole, just before mitral valve opening. Minimal LA volume (LAVmin) was determined at left ventricular end-diastole. LA areas  and superoinferior longitudinal diameters were measured from apical 4- and 2-chamber views. LA volumes were calculated by the following formula [1*A2/L = 0.85*A1*A2/L, where L is the shorter superoinferior diameter of the LA. LA volume index (LAVI) was calculated by dividing maximal LA volume by the body surface area .In order to evaluate LA remodeling LA size and LA function were evaluated before and after ablation. LA volumes were calculated by two-dimensional echocardiography by the biplane area-length method. Maximal LA volume  function was assessed by:A/VTIE+A) anda) the LA filling fraction (LAFF) which is the ratio of the velocity time integral (VTI) of the late diastolic A wave velocity of mitral inflow to the VTI of the early and late diastolic velocities of mitral inflow , measured by pulsed-wave TDE.b) septal and lateral velocities of the mitral annulus during atrial contraction (AaLA reservoir function was assessed by:max-LAVmin)/LAVmax) anda) LA total emptying fraction (LAEF = (LAVS/VTIS+D). Pulmonary venous flow was measured within right upper pulmonary vein.b) the systolic fraction of pulmonary venous flow  were measured by TDE, which characterize left ventricular relaxation. In the assessment of mean left ventricular filling pressure E/Ea ratios were calculated, using both the lateral, septal and average Ea velocity. Early (E) and late diastolic (A) velocities of mitral inflow, and deceleration time (DT) were measured by pulsed wave Doppler echocardiography, and E/A ratio was calculated. Systolic (S) and diastolic (D) velocities of pulmonary venous flow were measured and S/D ratio was also calculated.In the detailed evaluation of left ventricular diastolic dysfunction, we used the methods described in recent recommendations ,23. Septt-test was used to compare means of continuous variables between unrelated groups. Chi-square analysis was used to compare patient group characteristics with discrete variables. Paired-sample Student's t-test was used to evaluate changes in echocardiographic parameters of LA size and function and of LV diastolic function during the follow-up period within groups. A p < 0.05 was considered statistically significant for all calculations. Statistical analysis was performed using SPSS  version 13.0.Data are shown as mean ± standard deviation (SD) . Unpaired The clinical success rate, as it was defined previously with no recurrence after the 3-month blanking period , was 23 15 patients were totally free of arrhythmias throughout the first 12 months of follow-up (the AF-free group). The other 21 patients (the recurrent group) experienced some recurrence of atrial arrhythmias. Only early (within 3 months after treatment) recurrence in 8, only between 3 and 12 months after treatment recurrence in 4, both early and 3 to 12 months recurrences in 9 patients were detected.36 consecutive patients were enrolled in the study; there were 26 males and the mean age was 57.4 ± 8.9 years. The most frequent symptom was palpitation; signs or symptoms of congestive heart failure were not present. 27 patients (75%) had hypertension. The average time period from the first recognition of AF was 6.7 ± 7.3 years (range 0.5-20).p < 0.05) before cryoballoon catheter ablation. At baseline, patients' age, gender, prevalence of concomitant diseases such as hypertension, diabetes mellitus, hyperlipidemia and obesity were not significantly different between the recurrent and AF-free groups (Table In patients who later developed a recurrence (recurrent group), had a longer duration of atrial fibrillation . Left ventricular and left atrial dimensions, and left atrial functional parameters, TDE parameters of LV diastolic dysfunction and normal values from the literature ,23-25 arp < 0.05) , E/Ea ratios, LA size and LA pump function were not significantly different between the recurrent and AF-free groups. However, the left atrial reservoir function by left atrial total emptying fraction was significantly lower in the recurrent group , the maximal left atrial volume , LAVI  and the maximal left atrial longitudinal diameter  had all increased  and LA pump function assessed by left atrial filling fraction  had decreased   Figure .Our study was the first in which left atrial structural and functional remodeling were examined in detail in patients who had cryoballoon catheter ablation for paroxysmal atrial fibrillation. Successful ablation prevented progressive LA remodeling, whereas the left atrium enlarged in patients with recurrent atrial arrhythmias.In the present study, left atrial size before cryoballoon ablation did not affect the success rate; there was no difference in LA size before ablation between AF- free and recurrent group of patients. These results are similar to a study by Rodrigues et al.  in whichWe found that at one year after unsuccessful cryoballoon catheter ablation left atrial size had increased. In contrast, successful ablation had prevented progressive LA dilatation. The meta-analysis of 17 studies by Jeevanantham et al.  confirmeIn patients with PAF, LA structural reverse remodeling has not always been observed even after successful catheter ablation. Beukema et al.  found thIn our study the left atrial filling fraction--a parameter of LA pump function--decreased 12 months after ablation in the recurrent group. After successful cryoballoon ablation, LA pump function did not change.In previous studies, after successful radiofrequency ablation in patients with paroxysmal and/or persistent AF, LA pump functional parameters, such as LA filling fraction ,11, and In PAF patients who underwent successful radiofrequency catheter ablation, similarly to our study, Aa velocities did not change in a study by Rodrigues et al. 8 ± 2 month after RFCA . In studIn our study the left atrial total emptying fraction--a variable of left atrial reservoir function--was lower at baseline and during follow-up in the recurrent group, but it did not change in either group.After 12 months the pulmonary venous systolic fraction--a parameter of LA reservoir function--decreased in the recurrent group. After successful cryoballoon ablation, it did not change. In other studies ,33 as coIn PAF patients who underwent successful radiofrequency catheter ablation, left atrial total emptying fraction did not change significantly after 8 months  or one yLeft ventricular diastolic function did not affect the success rate in the present study; no difference was found between the groups regarding LV diastolic function at baseline.We did not demonstrate any change in Ea velocities during the one-year follow-up in the recurrent, or in the AF-free group, similarly to the study of patients with successful PAF ablation by Donal et al. . HoweverIn our study the E/Eaaverage was increased at one year after cryoballoon catheter ablation in the recurrent group. E/Ea ratio was shown to decrease ,7 or didThe number of patients in our study was relatively small, similar to other studies of this topic ,7,26; buThe post-procedure monitoring of AF recurrences was fairly intensive in our present study; but it may have missed asymptomatic recurrences.We used 2DE to calculate LAV, while measurements with magnetic resonance imaging (MRI) or multislice computerized tomography (CT) are more accurate: all echocardiographic methods systematically underestimate LAV ,35. HoweSeveral approaches are used to measure LAV by 2DE, which makes the comparison of our data with other studies more challenging. LA volumes measured in our study seemed to be larger than some other studies ,38, whicUsually, 20 to 30% of the patients with clinically unsuccessful ablation undergo a redo procedure. According to the definition of the Ablation Consensus Statement  in our sIn patients whose nonvalvular paroxysmal atrial fibrillation recurred within one year after cryoballoon catheter ablation, left atrial size increased, left atrial pump and reservoir function declined, and the left ventricular filling pressure increased, all related to left atrial remodeling (progressive enlargement). In contrast, successful cryoballoon catheter ablation prevented progressive left atrial remodeling.It would have been interesting to compare the effect of cryoballoon catheter ablation and RFCA on the LA remodeling which can be subject of a further study.1: Left atrial area from apical four-chamber view; A2: Left atrial area from apical two-chamber view; Aalat: Late diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the lateral mitral annulus; Aasept: Late diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the septal mitral annulus; AF: Atrial fibrillation; CCA: Cryoballoon catheter ablation; CHADS2-score: Congestive heart failure; hypertension; age; diabetes mellitus; stroke; CT: Computed tomography; D: Diastolic velocity of pulmonary venous flow; DT: Deceleration time; E: Early diastolic velocity of mitral pulsed wave Doppler inflow; Eaavg: Average value of septal and lateral early diastolic velocities measured by pulsed-wave tissue Doppler echocardiography; Ealat: Early diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the lateral mitral annulus; Easept: Early diastolic velocity measured by pulsed-wave tissue Doppler echocardiography at the septal mitral annulus; EF: Ejection fraction; LA: Left atrium; LAFF: Left atrial filling fraction; LAEF: Left atrial total emptying fraction; LAV: Left atrial volume; LAVmax: Left atrial maximal volume; LAVmin: Left atrial minimal volume; LAVI: Left atrial volume index; LV: Left ventricular; MRI: Magnetic resonance imaging; PAF: Paroxysmal atrial fibrillation; PVSF: Systolic fraction of pulmonary venous flow; RFCA: Radiofrequency catheter ablation; S: Systolic velocity of pulmonary venous flow; SD: Standard deviation; TDE: Tissue Doppler echocardiography; VTI: Velocity time integral.2DE: Two-dimensional echocardiography; A: Late diastolic velocity of mitral pulsed wave Doppler inflow; AThe authors declare that they have no competing interests.ML and TE introduced the study idea. AK, AM, CF made substantial contributions to study conception and design, and performed the ablations. TE acquired the transthoracic echocardiography images, performed the analysis and wrote the manuscript. AT acquired the transoesophageal echocardiography images and reviewed and helped to revise the manuscript. MD helped in the interpretation of the results and statistical analysis. All authors read and approved the final manuscript.


Mean systolic blood pressure and heart rate were slightly increased in the alcohol group compared to controls . While there was no significant difference in terms of LVEF  or shortening fraction , global LS was significantly impaired . In addition, subjects who consumed alcohol had increased LV end-diastolic  and end-systolic volumes , along with depressed aortic time-velocity integral . According to multivariate linear regression analyses, blood alcohol level was the only factor significantly associated with global LS . Conclusion: Alcohol intoxication around festive days induces acute LV contraction abnormalities, which may be detected using global LS by speckle tracking at an earlier stage and more accurately than LVEF decreases.Objectives: We evaluated the ability of two-dimensional speckle tracking strain echocardiography to detect left ventricular (LV) systolic dysfunction as compared with LV ejection fraction (EF) in healthy subjects following acute alcohol intoxication. Methods and Results: In total, 25 healthy subjects were investigated using echocardiography 4–6 hours after the onset of alcohol intoxication at a regional festive gathering, and then compared to 23 healthy control subjects without alcohol consumption. Heart rate, blood pressure, blood alcohol level, LV volumes, EF, shortening fraction, E/A ratio, as well as global longitudinal strain (LS) were recorded. Mean blood alcohol level was 1.3 ± 0.3 g.L Previous studies have reported a depression in left ventricular (LV) contractility after acute ethanol consumption based on invasive hemodynamic approaches,7Myocardial deformation analysis using two-dimensional (2D) speckle tracking echocardiography has already been validated, showing high levels of reproducibility and accuracy in detecting subtle early LV systolic function abnormalities  in heart disorder patients without an altered EF.14Therefore, our study aimed to investigate the ability of 2D speckle tracking strain echocardiography to detect early LV systolic dysfunction as compared with conventional LVEF evaluation in healthy subjects after acute alcohol intoxication versus a control group of healthy nonintoxicated subjects.During a regional festive gathering, consecutive healthy men subjects admitted to the aid station were consecutively evaluated by the same observer using echocardiography, 3 to 4 hours after the onset of acute alcohol intoxication.A control group of volunteers, comprising medical students at our University Cardiologic Hospital, was recruited, given the condition that they had not consumed any alcohol for at least 10 days prior to the study.To be eligible as healthy subjects, subjects had to be free from any known cardiovascular disease, diabetes, and hypertension.The study excluded subjects presenting insufficient ultrasound image quality, defined as more than three LV segments being suboptimally visualized by conventional echocardiography.Echocardiographic measurements were performed by a second observer, blinded to the subjects’ levels of alcohol consumption.Systolic and diastolic blood pressures, heart rate, and blood alcohol level were systematically measured immediately prior to the echocardiography.In order to estimate the blood alcohol levels, a portable breathalyzer approved by the National Authorities was used, with measurements being repeated three times and their mean values determined.Written informed consent was obtained from all subjects. In accordance with the local ethical guidelines, this observational study was designed to be performed in the context of popular festivities.The subjects were examined in the left lateral decubitus position using a Vivid Q commercial ultrasound scanner  with phased-array transducers (M4S-RS).−1. Color Doppler recordings were obtained in order to exclude valvular dysfunction, and Doppler flow recordings were performed with a horizontal sweep velocity of 100 mm/sec.Thereafter, 2D data acquisitions were obtained, including parasternal long- and short-axis views and three standard apical views. For each view, three consecutive cardiac cycles were recorded during quiet respiration. Grey-scale recordings were optimized for LV evaluation at a mean frame rate of at least 50 secAll standard measurements were taken by the same observer using dedicated software , including percentage of LV fractional shortening, LV outflow tract time-velocity integral, peak velocity of E- and A- waves of the mitral inflow, as well as tissue Doppler analysis of max velocity E’ peak at the lateral mitral annulus. E/E’ ratio was calculated to represent LV end-diastolic pressure. Based on apical four- and two-chamber views, LV volumes and EF were measured according to Simpson's rule. All measurements were made by averaging three cardiac cycles.For longitudinal strain (LS) analysis, the software automatically tracked the contour on subsequent frames after three endocardial markers were placed in an end-diastolic frame. Adequate tracking could be verified in real time and corrected by adjusting the region of interest or manually correcting the contour so as to ensure optimal tracking. In addition, LS was assessed in apical views. Average LS was calculated for the 17 segments in relation to the strain magnitude at aortic valve closure. Longitudinal systolic deformation was characterized as shortening, and using the strain definition, systolic indices yielded a negative value.The second observer performed all the echocardiographic measurements, which were later repeated blindly for each parameter. The data were also analyzed by a third blinded observer for 10 of the subjects. Intraobserver reproducibility was calculated using the average difference between 10 measurements, and interobserver reproducibility was assessed as the absolute difference divided by the average of the two observations for all parameters.All statistical analyses were performed using SPSS for Windows . All data were expressed as mean ± standard deviation.t-tests or the Mann-Whitney test where necessary. A P-value of <0.05 was considered statistically significant. Univariate and multivariate linear regression analyses were performed in order to identify potential links with global LS. The following independent variables were examined: systolic and diastolic blood pressure, heart rate, blood alcohol level, LV shortening fraction, biplane LV end-diastolic volume, biplane LVEF, aortic time-velocity integral, and E/E’.Between-group comparisons were made using paired Among the 25 screened subjects with acute alcohol intoxication, two were excluded from the analysis on account of having at least nonvisualized three LV segments, considered to be of insufficient image quality. The healthy controls without alcohol consumption consisted of 23 subjects.−1. Mean systolic blood pressure and heart rate were slightly higher in the alcohol group compared to controls, with the differences being statistically significant . Clinical characteristics of the two study groups are summarized in The population participants who consumed alcohol were all men, with a mean age of 25 ± 8 years. Mean blood alcohol level was of 1.3 ± 0.3 g.LEchocardiographic characteristics of the study population are summarized in However, global LS was significantly lower in subjects with alcohol intoxication , larger LV volumes (P < 0.05), and lower aortic time-velocity integral. There was no linear relation between global LS and LV volumes or blood pressure, nor was there any correlation between blood alcohol levels and clinical or other echocardiographic parameters.Mean intra- and interobserver variability of global LS was 7% and 8%, respectively.The results of univariate analysis  for the different parameters and their relation to global LS are provided in In a multivariate analysis, regarding the separate contribution to global LS of each parameter among all parameters selected, only alcohol intoxication was found to significantly and inversely contribute to global LS  .In this study, our main finding was that myocardial LS analysis using 2D speckle-tracking echocardiography allowed us to detect early LV systolic dysfunction immediately after acute alcohol intoxication in men, whereas LVEF and LV shortening fraction did not differ from those of control healthy subjects.The conventional evaluation of LV systolic function by means of shortening fraction or EF is limited by the percentage variability of measurements (10–15%). The assessment of LV longitudinal deformation using 2D speckle tracking has been largely validated against sonomicrometry and MRI as reference methods.Moreover, global LS analysis, also known as automated function imaging, permits the exploration of the myocardial pathophysiology in new ways, particularly by detecting early alterations in the longitudinal component of LV systolic function, while the radial component is considered normal.In studies on animals and healthy subjects, alcohol intoxication was shown to cause a dose-dependent impairment of cardiac contractility,16Several published studies reported a depression in LV contractility following acute ethanol consumption based on invasive hemodynamic approaches,4Delgado et al. investigated the effects of oral doses of whiskey on LV function in a group of normal volunteers (n = 13).More recently, a clinical MRI study reported a reversible myocardial injury as defined by myocardial hyperhancement after binge drinking, but without any concomitant decrease in LV systolic function.LVEF was evaluated in 2D using biplane Simpson's method, although 3D volume quantification might have been more accurate for quantifying EF and volumes. As only male subjects were included in our study, the effects of alcohol intoxication on LV systolic function in women were not assessed. In this study, we did not perform serial echocardiography on the alcohol intoxicated subjects. This should have strengthened our results.Preload and afterload modifications may exert an impact on LV strains. In severe aortic stenosis or hypertensive cardiopathy, afterload elevation was shown to influence more specifically the longitudinal component of LV systolic function, due to the greater radius of curvature of longitudinal fibers. Soon after alcohol intoxication in healthy subjects, blood pressure, heart rate, and volumes were shown to be increased. We, therefore, assumed that preload and afterload elevations may have an impact on global LS. However, multivariate regression analyses demonstrated that blood alcohol levels alone were significantly related to global LS, whereas blood pressure, heart rate, LVEF, and LV volumes were not.Global LS by speckle tracking echocardiography allows for a more accurate detection of early LV systolic dysfunction after festive alcohol intoxication compared to LVEF, with the results being independent from blood pressure, heart rate, and LV volumes variations.


ST elevation acute myocardial infarction (STEMI) is frequently associated with reciprocal ST depression in the contralateral ECG leads. The ECG remains a primary diagnostic factor in the hyperacute treatment of AMI. There has been longstanding debate over the relevance of reciprocal ECG changes in AMI.CMR can retrospectively determine myocardial area at risk (AAR), namely, the area of myocardium that is susceptible to infarction prior to opening the infarct-related artery. T2-weighted (T2w) imaging can be combined with measures of infarction by late gadolinium enhanced (LGE) imaging to derive myocardial salvage, a measure with established prognostic relevance. We hypothesised that reciprocal ECG change reflects larger AAR as defined by CMR.Patients after primary percutaneous coronary intervention for first STEMI underwent CMR at 1.5T within 3 days of reperfusion. Presenting ECGs were assessed for presence or absence of reciprocal change, defined as ≥1mm ST depression in ≥2 inferior leads for anterior STEMI, or ≥2 anterior leads for inferior STEMI. Patients with posterior ECG changes were excluded from analysis. Infarcted tissue was defined as hyperenhancement ≥2 standard deviations (SD) above remote myocardium on LGE imaging. AAR was defined on T2w images, defined as the mass of myocardium with signal intensity ≥2 SD above remote, normalized to LV myocardial mass. Myocardial salvage was calculated as (AAR mass - infarct mass), and myocardial salvage index as .Thirty-five patients had ECGs and images suitable for analysis. There were no significant differences in patient demographics Table . PatientPatients with STEMI presenting with reciprocal ECG changes have significantly larger AAR, and significantly higher myocardial salvage and salvage index than those without. Reciprocal ECG changes may be a marker of larger volumes of myocardium at risk, and may also denote patients with larger potential for salvage with revascularization. There was no relationship to infarct size, presumably as other factors, such as time to revascularization and TIMI flow post-procedure will influence the degree of myocardium infarcted.S.P is funded by British Heart Foundation fellowship (FS/10/62/28409)S.P and J.P.G receive a research grant from Philips Healthcare


Dobutamine and esmolol infusions led to inversely correlated changes in hemodynamic measurements of LV function. Apical but not basal rotation and diastolic rotation rate were decreased by esmolol and increased by dobutamine. The LV twist correlates well with Emax (r = 0.83) and Emax/Ea (r = 0.80). Apical diastolic rotation rate also correlates with dP/dtmin (r = −0.63), τ (r = −0.81), and LV stiffness (r = −0.52). LAD ligation decreased systolic and diastolic LV rotation in apical (P < 0.05), but not basal myocardium. Occlusion of the inferior vena cava, to reduce preload, increased apical rotation in systole and diastole. LV rotational parameters measured by STE provide quantitative and reproducible indices of global LV systolic and diastolic function during acute changes in hemodynamics.Although rotational parameters by speckle tracking echocardiography (STE) have been previously compared to sonomicrometry and cardiac magnetic resonance imaging, few have examined the relationship between left ventricular (LV) rotational mechanics and intraventricular measures of load-independent contractility, LV stiffness, or ventriculoarterial coupling. The aim of this study was to compare the changes in LV rotational indices to intraventricular pressure–volume (PV) relationships under a range of inotropic states induced by pharmacological interventions, acute ischemia, and changes in preload. In nine pigs, simultaneous echocardiographic imaging and LVPV measurements were performed during pharmacologically induced high or low inotropy and during acute ischemia by ligation of the left anterior descending coronary artery (LAD). Maximal ventricular elastance (E The complexity of cardiac disease states treated clinically in the modern era has seen a steady increase. This can be partly attributed to the aging population and the wide array of cardiomyopathies seen in clinical practice. Despite advances in diagnostic instrumentation, accurate clinical assessment of left ventricular (LV) systolic and diastolic function remains challenging. Establishing pressure–volume (PV) relationships represents the gold standard for global assessment of LV systolic and diastolic function and yields a number of parameters describing cardiac function including end-systolic and -diastolic PV relationships  have facilitated the quantification of myocardial systolic and diastolic function . Clinically, one needs to understand myocardial performance which includes systolic and diastolic functional indices, and ultimately generates cardiac output. Therefore, a more intricate assessment of cardiac function that more closely mirrors invasive measurements with an LV volumetric catheter is needed. The aim of this study was to compare the changes in LV rotational indices to intraventricular pressure–volume relationships under a range of inotropic states induced by pharmacological interventions, acute ischemia, and changes in preload. We chose to record both load-independent and dependent parameters as they pertain to basic physiology and clinical practice, respectively.The animal study was approved by the Chancellor's Animal Research Committee at University of California, Los Angeles and animals were treated in compliance with the National Institutes of Health guidelines for the care and use of laboratory animals. Nine Yorkshire pigs weighing 40–45 kg were anesthetized intramuscularly with ketamine (15–25 mg/kg) and xylazine (2 mg/kg) and mechanically ventilated via endotracheal intubation. Anesthesia was maintained by inhaled isoflurane (1–2%) and intermittent intravenous boluses of fentanyl (5–10 μg/kg). The electrocardiogram was monitored from limb leads. The femoral artery and jugular vein were cannulated for blood pressure measurement and drug infusion. The animals underwent median sternotomy, and a snare was placed around the inferior vena cava (IVC) for preload manipulation. Occluding snares were placed around the left anterior descending (LAD) coronary artery.A 5F pigtail 12-pole multielectrode combination conductance-pressure catheter  was placed in the left ventricle (LV) via the right carotid artery and connected to a conductance processor  for continuous measurement of LV pressure and volume , dP/dtmax/EDV, a sensitive isovolumic phase measure of LV contractility  was calculated as ESP divided by stroke volume (SV) . Diastolic function was assessed by the LV end-diastolic pressure (LVEDP), isovolumetric relaxation time constant (τ), and the minimum rate of LV pressure change (dP/dtmin) , where c is the diastolic PV coefficient, β is the chamber stiffness constant, and LVEDV is LV end-diastolic volume. The parameters β and c represent load-independent indices of diastolic function  with a 10 MHz transducer. Image quality was improved using a 5 × 3 cm section of preharvested pig liver affixed to the echo probe with parafilm. Echocardiographic and hemodynamic data were acquired sequentially for each manipulation, while assuring similar hemodynamics between the two. A phase array transducer (GE 10S) with frequency of 10 MHZ, frame rate of 70 per sec, and sector widths manually adjusted to optimize speckle quality, was used. Three cardiac cycles were recorded for subsequent offline analysis. LV rotation measurements were obtained using speckle tracking software  at the basal  and apical (at the level when papillary muscles just disappear) levels. Counterclockwise rotation was defined as a positive angle and clockwise rotation as a negative angle when viewed from the apex toward the base. The accuracy of the image tracking software was verified manually.max. Hemodynamic parameters were allowed to stabilize for ∼15 min at each dose prior to data acquisition; following cessation of infusion of each drug, hemodynamic values were allowed to return to baseline prior to starting the next infusion. Following drug infusion hemodynamic parameters were allowed to return to baseline values, at which point, the LAD was then occluded for 30 min. Sequential STE images and PV measurements were acquired repeatedly during end-expiratory apnea on a mechanical ventilator. Data acquisition was repeated three times and averaged for each condition with >3-min intervals between measures. All animals were euthanized at the end of the study with pentobarbital (100 mg/kg) and KCl solution intravenously.The animals were stabilized for a 30-min period prior to baseline measurements. Hemodynamic and STE images were recorded at baseline and 30–35% reduction in end-diastolic volume by 1 min of IVC occlusion. A 30–35% decrease in preload was confirmed by the Millar catheter measurement of LVEDV. LV systolic and diastolic function were examined at baseline in addition to manipulated inotropic states: low inotropic state  and high inotropic state , titrated to a ∼20% change in dP/dtP < 0.05.Analysis was performed using Sigma Stat  and data are presented as mean ± SD. The hemodynamic and echocardiographic measurements were compared in the various experimental stages by use of repeated analysis of variance followed by the post hoc Bonferroni correction. Linear regression analyses were performed to determine relationships between echocardiographic and PV loop diastolic indices. Correlations between echocardiographic and PV parameters were determined using the Pearson correlation coefficient. Nonlinear terms were considered and included only if significant. Statistical differences were considered significant at Two independent observers processed echocardiography images for apical rotation in all animals. Each observer analyzed the same image two times. Intraobserver variability was determined by having one observer repeat the measures 1 month after the initial analysis. Interobserver and intraobserver variability was assessed using intraclass correlation coefficient (ICC) with 95% confidence intervals as we demonstrated previously  varied inversely with inotropic state measuring 0.061 ± 0.017 and 0.023 ± 0.011 during low and high inotropic states. Emax/Ea also significantly varied with low and high inotropy (0.66 ± 0.11 vs. 1.96 ± 0.22).Table Apical but not basal rotation and diastolic rotation rate were decreased by esmolol and increased by dobutamine suggesting that apical and basal rotation responded differently to pharmacological changes in inotropy.max decreased from 6.0 ± 0.8 at baseline to 2.4 ± 0.5 mmHg/mL during acute ischemia, while relaxation τ increased from 28 ± 7 to 39 ± 9 msec. During LAD occlusion, apical rotation decreased, while basal rotation did not change . Notably, STE diastolic parameters for apical and basal diastolic rotation rate also correlate well with Emax .To validate the accuracy of STE measurements in response to changes in inotropy, we correlated STE with PV parameters. The correlation coefficients between STE and PV loop systolic and diastolic parameters are summarized in Tables r = −0.81 and −0.59, respectively). The LV chamber stiffness constant (β) correlated better with apical than basal diastolic rotation rate (−0.65 vs. −0.36). Thus, apical LV diastolic rotation rate provided good surrogate measures of diastolic function, as demonstrated by good correlation with diastolic PV parameters.We then examined correlations between PV and STE diastolic parameters Fig. , Table 3max (15%) but increased dP/dtmax/EDV (18%); however, heart rate (HR), EDP, and relaxation time constant (τ) remained unchanged. During IVC occlusion, apical rotation significantly increased (23%), and time to peak apical rotation shortened (14%). The magnitude of apical diastolic rotation rate also increased (23%) during IVC occlusion.To determine whether STE parameters were affected by changes in preload, we measured PV loops and STE values during IVC occlusion. A 30–35% reduction in preload by IVC occlusion Table  predictaWe checked the reproducibility of apical rotation. The ICC for intraobserver variability was 0.92 while for interobserver variability was 0.86.max and dP/dtmax/EDV as well as ventricular–arterial coupling such as Emax/Ea. LV twist is also a sensitive parameter of systolic function during preload manipulation. Second, although previously correlated with isovolumic relaxation time constant (τ) , the last of which has remained controversial. Thus, LV diastolic rotation rate serves as a good surrogate measure of diastolic function. Although systole and diastole are likely coupled and each rotational parameter does not specifically indicate function during each phase alone, given the close correlation of LV twist and untwist with Emax, we suggest that the STE rotational parameters may be the most accurate noninvasive measures of global myocardial function.In this study, we demonstrate the validity of STE in determining cardiac functional parameters during pharmacological inotropic manipulation, acute regional cardiac ischemia, and acute preload changes. Several novel insights can be learned from this study. Although LV twist has been shown to be an accurate measure of systolic function, we have now shown that it also correlates well with load-independent indices of ventricular contractility such as Emax and dP/dtmax/EDV, suggesting that LV twist may serve as a sensitive marker of global systolic function.Speckle tracking analysis provides angle-independent information on motion and deformation of LV, which is a major improvement over standard echocardiographic approaches , whereas the images in the LV apex remained relatively stationary. In our study, the relationships between STE and PV loop parameters were better correlated at the apical level than at the base. The observed apicobasal differences in rotation are consistent with the known mechanical properties of the heart; however, possible motion artifacts cannot be completely excluded and would likely have been greater in basal rather than apical recordings.As this study was performed in accordance with National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, anesthesia was maintained to abolish the pain response at all times. The difficulty in assessing the depth of anesthesia is ubiquitous in studies of anesthetized animals and may affect the cardiovascular response to various hemodynamic manipulations.The present findings demonstrate that STE parameters correlate well with PV data under a wide range of cardiac inotropic states. LV twist and untwisting rates assessed by STE provide quantitative and reproducible indices of global LV systolic and diastolic function during acute hemodynamic changes. Thus, STE rotational parameters may serve as flexible clinical and research tools for assessment of heart function.


Electrocardiogram (ECG) gating is commonly used to synchronize imaging windows to diastasis periods over multiple heartbeats in magnetic resonance (MR) coronary angiography. Calibration of the ECG gating parameters is typically based on a cine cardiovascular MR (CMR) video of the beating heart. Insufficient temporal resolution in the cine-CMR method, however, may produce gating errors and motion artifacts.It was previously shown that tissue Doppler echocardiography (TDE) can identify accurate diastasis window timings by observing the movement of the interventricular septum (IVS). We present a new CMR technique, the Septal Scout, for measuring IVS motion. We demonstrate that cardiac gating windows determined by the Septal Scout produce sharper coronary MR angiography images than windows determined by cine-CMR.Wcine).9 healthy volunteers were scanned on a GE Optima 450w 1.5T MR system. Cine-CMR was acquired and used to identify the start and end times of the diastasis window (Wsep).The Septal Scout employs a one-dimensional steady-state free precession (SSFP) readout along the ventricular septum prescribed from the 4-chamber view. The Septal Scout data is processed to produce a septal velocity function, from which the diastasis window was determined  measurements of cross-sectional vessel profiles.Non-contrast-enhanced MR angiography was performed twice for each volunteer: once gated to WTDE) were determined from the IVS velocity measured in the 4-chamber view. Wsep and WTDE were compared using Pearson’s correlation.In addition, TDE was performed on a subcohort of 6 volunteers where diastasis windows (p < 0.05). Subjective assessment of sharpness also improved for the Septal Scout-gated scans (p < 0.01 for both observers). Lastly, Wsep and WTDE were highly correlated .MRA acquisitions were successful in all volunteers. Vessel segments produced smaller FWHM measurements and were deemed sharper when imaged during the Septal Scout gating windows (The MR Septal Scout technique was introduced and demonstrated to be more accurate at determining cardiac gating windows than cine-CMR, yielding sharper coronary MR angiography images. Magnetic resonance coronary angiography (MRCA) is a potential diagnostic tool for coronary artery disease (CAD). Compared to the current gold standard, x-ray angiography, benefits of MRCA include three-dimensional visualization of coronary vessel lumens, and not subjecting patients to the risks associated with catheterization ,2 and ioProspective cardiac gating remains the most effective tool for reducing cardiac motion artifacts in MRCA. The general principle behind cardiac gating is to synchronize, for each heartbeat, the imaging window with the diastasis period. Shechter et al. and Johnson et al. have measured coronary artery velocities during diastasis to be on the order of 10 mm/s ,5. SeverCardiac gating is most commonly facilitated by the use of (1) the electrocardiogram (ECG) for monitoring ventricular systole onset, and (2) a cine cardiovascular MR (CMR) video of a heartbeat obtained prior to the MRCA scan for finding the timing of diastasis relative to the ECG. Yet, the use of cine-CMR to determine ventricular diastasis may produce cardiac gating errors due to insufficient temporal resolution of the cine-CMR method.k-space lines acquired per segment (of k-space) per heart beat, herein denoted lines per segment (LPS), multiplied by the acquisition time of each k-space line, commonly known as the repetition time (TR). The number of segments used to complete k-space coverage dictates the number of heartbeats required for the total scan duration. For example, consider the cine parameters: heartbeat duration, 960 ms; field of view (FOV), 35 cm; number of frames, 30; TR, 4 ms; partial Fourier acquisition matrix size, 160 × 256; and LPS, 16. The cine acquisition would span 10 heartbeats, have a true temporal resolution of 64 ms. Extending this example with approximate motion parameters, a mid right coronary artery moving at a peak velocity of 12 cm/s during rapid filling and decelerating constantly over 100 ms toward rest during diastasis will traverse 1.5 mm in the 50 ms preceding diastasis. The reverse motion may be observed transitioning from diastasis to atrial contraction. Therefore, during transitional cardiac phases pertinent to ECG gating, the conventional cine acquisition may not provide the sufficient frame rate to resolve the motion of an RCA segment. In addition to inadequate temporal resolution, cine acquisitions are susceptible to temporal data-mixing if the subject’s heart rate varies during the scan duration.The temporal resolution of a conventional cine acquisition depends on the number of In this paper, we present a new CMR technique, the Septal Scout, for determining the timing of the diastasis period. The Septal Scout measures ventricular septal motion. We demonstrate that cardiac gating windows determined by the Septal Scout produce sharper MRCA images than windows determined by cine-CMR. To facilitate a user-independent assessment of the diastasis period from cine-CMR data, an empirical approach was chosen based on identifying a plateau period of high frame-to-frame correlations during diastole .This study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre, and all volunteer subjects provided written informed consent prior to participation in the study. We studied 9 healthy male volunteers of age 30 ± 4 years. Each volunteer performed a series of breath holds for 15 to 20 heartbeats, during which non-contrast-enhanced MRA was performed. The volunteers were instructed to perform the breath holds in a consistent manner with end-expiration chest positions.All CMR was performed on a GE Optima 450w 1.5 T MR system using a 32-channel cardiac phased-array coil. The coronary artery imaging protocol consisted of 4 steps: (1) Localization: MR-Echo, the stock realtime sequence, was used to find and bookmark the short-axis 2-chamber view, and the long-axis 2-chamber through the left ventricle; (2) Cine CMR gating window calibration: the bookmarked views were used to prescribe a 4-chamber slice for a cine acquisition, from which the diastasis imaging window is determined; (3) MR Septal Scout gating window calibration: from the 4-chamber cine view, a slice is prescribed along the ventricular septum for fast, projection imaging. From this Septal Scout data, the timing of diastasis is also determined; and, (4) High-resolution MRA acquisition: a 4-cm slab is prescribed obliquely from above the aortic valve to the right lateral atrioventricular (AV) groove for 3-dimensional (3D) SSFP imaging. The prescription is intended to cover: the left and right coronary ostia; the entire right coronary artery up to the posterior-lateral branch; the left main (LM), proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries; and, the associated branches including the proximal conus and sino-atrial (SA) nodal arteries. The latter 3 steps are detailed below.Wcine) as determined by cine-CMR. This method of using inflection points is intended to capture the points of approach toward and departure from a diastasis period that is presumed to (1) exist; and (2) be stationary according to the cine-CMR images. In our experience, compared to threshold methods, this approach is more robust against minor motion variations observed within diastasis.To determine the optimal data acquisition window relative to the R-peak of the ECG, a long-axis 4-chamber cine was acquired using a breath-held SSFP sequence with an in-plane resolution of 1.4 × 1.8 mm and 5-mm slice thickness . The cine MR images were cropped by a rectangle that encompassed the 4 chambers of the heart across all frames to reduce the amount of stationary background tissue. The images were exported to MATLAB® and processed using a custom script. Frame-to-frame correlation coefficients (CC) were calculated , where IQR is the interquartile range representing the difference between the third and first quartile marks. A two-tailed test with P-values ≤ 0.05 was interpreted to indicate statistical significance.p < 0.001). Figure In the sub-cohort component of this study comparing the Septal Scout to TDE of the IVS, high agreement was observed in the estimation of the start and end times of the diastasis window. The correlation coefficients of the two techniques for both the start and end times were greater than 0.98  between the median widths of 3.6 [0.7] mm versus 4.1 [0.6] mm, respectively. The small vessel segments were also measured to have a significantly (p = 0.03) smaller FWHM in the Septal Scout group than in the cine-CMR group, with median widths of 2.1 [0.2] mm versus 2.4 [0.2] mm, respectively.Vessel segments were sharper when imaged during the Septal Scout gating windows for both the large and small diameter groups . Sample images and the corresponding gating windows are shown in Figures Subjective assessment of vessel sharpness also showed an improvement for the Septal Scout-gated scans. Large vessel segments from the Septal Scout group obtained higher sharpness scores from both Observer 1 .There were no significant differences in SNR between the MRCA images acquired with the Septal Scout and cine-CMR techniques  imaging tissues in the Septal Scout plane which is perpendicular to the 4-chamber plane, and (2) acquiring 1D vs 2D data, it is believed that the superior temporal resolution of the Septal Scout is the most important factor for its improved performance.In the subcohort comparison between the Septal Scout and TDE methods, the timing differences of the estimated diastasis periods sometimes reached as high as 15–20 ms. Since the Bland-Altman plots  may affect the FWHM comparison if the actual vessel orientations were significantly different between the cine-guided vs. the septal scout-guided acquisitions. For example, if one method produced a gating window during which a vessel segment is oriented much more perpendicular to the slice orientation of the 3D image acquisition, the vessel cross-sections would appear sharper due to the higher in-slice resolution. We did not, however, observe this effect. The intrinsic resolution was near isotropic. And, this effect should not have systematically favoured one method of the study in particular.The FWHM assessment of vessel profiles required the reformatting of vessel segments into a cross-sectional orientation. Theoretically, the asymmetric intrinsic resolution of the MRA data  wall navigator presented in the past by Stuber et al. . A majorThe performance of the Septal Scout in the presence of cardiac pathology has yet to be tested. In general, septal wall defects will likely change the relationship between septal and ventricular diastasis. One particularly problematic condition is known as the Septal Bounce, which is a paradoxical bouncing motion of the IVS initially toward and subsequently away from the LV during the beginning of diastole . This coIn our future work, we intend to explore the use of the Septal Scout to determine the onset of ventricular systole, which is currently detected by the R-peak of the ECG. This provides the benefit of not having to maintain an ECG signal to perform cardiac-gated MR imaging. Currently, the ECG signal may arbitrarily deteriorate due to loosened connections at the chest electrodes; also, R-peak detection may fail due to significant T-wave amplification , which mIn this chapter, the MR Septal Scout was shown in a healthy volunteer study to be effective at determining accurate cardiac gating windows. Specifically, this new technique is consistently more accurate than the cine-CMR method, the current clinical standard. The improvement in cardiac gating accuracy provided by the Septal Scout lead to sharper coronary MRA images. Furthermore, the Septal Scout was shown to provide diastasis windows that are in close agreement with those provided by TDE measurements of septal motion.1D: One-dimensional; 2D: Two-dimensional; 3D: Three-dimensional; AV: Atrioventricular; CAD: Coronary artery disease; CC: Correlation coefficient; CMR: Cardiovascular magnetic resonance; CMR-CGS: Cardiovascular magnetic resonance based cardiac gating system; ECG: Electrocardiogram; FOV: Field of view; FWHM: Full width half maximum; HRV: Heart rate variability; IQR: Inter-quartile range; IVS: Interventricular septum; LAD: Left anterior descending (artery); LCx: Left circumflex (artery); LM: Left main (artery); LV: Left ventricle; MR: Magnetic resonance; MRA: Magnetic resonance angiography; RCA: Right coronary artery; RF: Radio-frequency; ROI: Region of interest; SNR: Signal to noise ratio; SSFP: Steady state free precession; TDE: Tissue Doppler echocardiography; TE: Echo time; TR: Repetition time; LPS: Lines per segment.This work was supported in part by GE Healthcare. The authors declare that there are no other competing interests.GL and GAW contributed in the design of the study and drafted the manuscript. GL coordinated the study and performed the statistical analysis. All authors contributed in discussions and approved the final manuscript.


Megaptera novaeangliae) song chorusing occurring outside the breeding grounds are becoming more common, but song structure and underwater behavior of individual singers on feeding grounds and migration routes remain unknown. Here, ten humpback whales in the Western Antarctic Peninsula were tagged in May 2010 with non-invasive, suction-cup attached tags to study foraging ecology and acoustic behavior. Background song was identified on all ten records, but additionally, acoustic records of two whales showed intense and continuous singing, with a level of organization and structure approaching that of typical breeding ground song. The songs, produced either by the tagged animals or close associates, shared phrase types and theme structure with one another, and some song bouts lasted close to an hour. Dive behavior of tagged animals during the time of sound production showed song occurring during periods of active diving, sometimes to depths greater than 100 m. One tag record also contained song in the presence of feeding lunges identified from the behavioral sensors, indicating that mating displays occur in areas worthy of foraging. These data show behavioral flexibility as the humpbacks manage competing needs to continue to feed and to prepare for the breeding season during late fall. This may also signify an ability to engage in breeding activities outside of the traditional, warm water breeding ground locations.Reports of humpback whale ( Megaptera novaeangliae), one of the best-studied baleen whales, song is primarily produced on the breeding grounds, during the time of the life cycle in which males are competing for mating opportunities with females.Migratory species frequently exhibit distinct behaviors during different phases of their migratory cycle. For example, many baleen whale species have separate breeding and feeding grounds, and behavior is believed to be largely discrete between the two. In humpback whales , has been reported from several feeding areas and migration routes around the world Most of these studies also describe data recorded by remote hydrophones located in the northern hemisphere. While these instruments provide a measure of when humpbacks are present, overlap in chorusing can make it challenging to isolate a complete song produced by one individual to investigate its structure. Also, no data exist that describe the non-acoustic behavior of an individual whale during singing on the feeding grounds. Understanding the behavior and movements of individual whales during these time periods helps inform our interpretation of this off-season song.In this study we describe the results from two multi-sensor suction-cup tag deployments on humpback whales in an Antarctic feeding ground, the acoustic records of which contain loud song. These data are the first descriptions of a single individual's song structure from the Antarctic or any other feeding ground, and also of the underwater dive behavior of whales during this song production. We describe the structure and organization of the song recorded, compare the song patterns between the two individuals, and discuss whale behavior with respect to potential overlap or switching between sound production and feeding activity in a single location.RVIB Nathaniel B Palmer.We tagged ten humpback whales with non-invasive, suction cup acoustic tags DTAGs  in the wPalmer at night via a VHF radio signal from the DTAG.Tags were deployed for 24-hour periods, and during that time they continuously recorded acoustics (64 kHz sampling rate) as well as behavioral data from a suite of temperature, pressure, accelerometer, and magnetometer sensors . During daylight hours, tagged whales were visually tracked from small, rigid-hulled inflatable boats (RHIBs) conducting focal-individual follows Acoustic records were visually scanned for periods of song by two experienced acoustic analysts using the eXtensible Bioacoustic Analysis Tool (XBAT) It is difficult to definitively ascribe calls recorded on a tag to the focal animal because sounds produced by another animal in close proximity could also appear as intense sounds on the tagged animal's acoustic record Sound production was related to behavior by integrating the individual song units with the kinematics record based on time. Periods of song were overlaid on the dive profile to compare timing of song production with tagged animal depth and dive behavior. In addition, the locations of presumed foraging lunges were detected automatically using the algorithm described in Ware et al. All field research was permitted under the U.S. Marine Mammal Protection Act by the National Marine Fisheries Service Permit 808–1735, the Antarctic Conservation Act Permit 2009-014, and Duke University Institutional Animal Care and Use Permit A041-09-02.Background song was evident in the acoustic record of all ten tagged whales. In addition, the records of two whales (“mn132a” and “mn133a”) contained loud and clear song from an individual, for substantial lengths of time. Both of these whales were part of a closely associated pair when first tagged, and later on, whale mn132a was in a group of three animals during the first two bouts of song. We were not able to track the whales visually after sunset , so we do not know how many other animals, if any, were in close proximity during later bouts of sound production. Both of the tagged animals remained in Wilhelmina Bay  and songReceived levels of song units, calculated at the tag's location on the animal's back and over the full recording bandwidth, ranged between 111 and 159 dB re 1 µPa RMS (mean 139 dB re 1 µPa over 2811 units for mn132a and mean 138 dB re 1 µPa over 1874 units for mn133a). We did not observe any obvious association between RL and depth, time of day, or neighboring unit RLs (adjacent in time within the song).We named units based on their acoustic properties, using terms such as broadband burst (BB), pulsed (P), long , short , and high . For example, alternating long and short units would be labeled “L/S”. The two whales produced similar phrases, and shared themes and overall structure, including five identifiable and organized themes . The L/SGeneral structure on both records adhered roughly to the following pattern of themes: BB – PT – L/H – LM – L/S. One of the unique aspects of this dataset is the ability to examine the behavior of animals under water during the song recording. These results confirm that humpback whales commonly sing on the feeding grounds in the Western Antarctic Peninsula during late fall, as all tag records contained at least minimal background chorusing. Deployment of DTAGs allowed us to analyze song structure at the level of an individual, something that has not been addressed with remotely collected data documenting song chorusing. Through these tag data we also gain a unique perspective in terms of the underwater diving and movement behavior of whales during times of song production.Given that song is less prevalent on the feeding grounds, the level of structure in the song we recorded was higher than expected. We found a clear pattern of themes sung in a specific order, which is characteristic of humpback whale song as first described by Payne and McVay However, our recordings of off-season, or perhaps more accurately, shoulder-season song on this Antarctic feeding ground were not as continuous as song on the breeding grounds during the breeding season, where singers often sing for hours at a time We do not know for certain the breeding ground(s) of this population of humpback whales. Evidence of linkage between the Western Antarctic Peninsula humpbacks and the breeding ground off the coast of Bahia, Brazil has been gathered via satellite tracking Many of the focal whales observed during this research exhibited frequent periods of social activity in addition to feeding, including the two animals discussed here. Song production in a group of three adults (as was the case during the first two bouts of song production on the record of mn132a) is unusual in comparison to the breeding grounds and migration routes, where solitary singers or singers escorting mother/calf pairs are the norm The close overlap between singing and feeding in the record of whale mn133a is surprising. As noted above, it is possible that the song during this portion of the record is actually produced by a companion whale in close proximity. If this were the case, the two individuals would have had to maintain a relatively close fixed-distance association for long periods in order for the song to appear to have been from one animal continuously, or the song levels on the tag may have faded out completely as the other  whale drifted away. As described in the results section, unit received levels did vary over a range greater than 40 dB. However, these levels did not fluctuate in a regular way, i.e. increasing steadily as an associate drifted closer or decreasing steadily as an associate drifted away. Humpback whales are in fact known to vary their source levels during song production. Au and colleagues documented fluctuations of 10 dB re 1 µPa RMS within a given unit type from a single individual, and 22 dB re 1 µPa RMS of variation overall across three individuals and several unit types, as measured using a vertical array with stationary animals Regardless, even if it were a companion whale singing, whale pairs often engage in similar behaviors when associated Thus, this work highlights the issue of tradeoff between foraging and breeding/display behavior while still on the feeding grounds. Both animals appear to have switched between foraging and breeding/display behavior over the course of a 24-hour period, with even a conservative interpretation indicating that groups of animals may have some individuals feeding while others actively engage in mating displays. These results combined with the increasing number of reports of chorusing recorded on humpback feeding grounds Given the large amount of food available Humpback whale behavior may be more tied to the time of year than to physical location, in which case this behavioral tradeoff between feeding and mating behaviors would be a common dilemma faced by whales remaining on the feeding grounds later in the year due to varying environmental conditions. Recent work on fin whale song patterns in the Arctic has shown fin whale presence much later into the year than previously thought Acoustic File S1Representative song phrases (.wav). Example phrases for each of the two songs (Acoustic file S1 = record of mn132a and (WAV)Click here for additional data file.Acoustic File S2Representative song phrases (.wav). Example phrases for each of the two songs (Acoustic file S1 = record of mn132a and (WAV)Click here for additional data file.


The effectiveness of anthracycline chemotherapy is limited by dose dependant cardiotoxicity. Current protocols reduce the cumulative dose, however subclinical myocardial damage may still manifest years after cessation of therapy. The most serious side effect is dilated cardiomyopathy with pathological changes of fibrosis. The potential presence of fibrosis in this remodelling is unknown.The aim of this study was to use cardiac MRI to characterize subclinical cardiac abnormalities (changes in left ventricular (LV) morphology and extent of diffuse fibrosis) in childhood cancer survivors.Patients with previous anthracycline therapy for childhood cancer and in remission for at least 2 years underwent cardiac MRI on a 1.5T Siemens Sonata scanner to assess LV function and mass (indexed to body surface area). Changes in myocardial T1 values from baseline to 15 minutes post bolus injection of Gd-DTPA (0.125 mmol/kg) was used to estimate the tissue concentration of contrast, reflecting diffuse fibrosis ([Gd ]= {1/T1(15 min) - 1/T1 (baseline)}/4.35, in mmol). Myocardial T1 values were quantified in 3 mid-ventricular short axis slices using a custom saturation recovery single shot SSFP pulse sequence with 10 saturation recovery times spanning the cardiac cycle, acquired in one breath-hold per slice. Myocardium was segmented using a modified AHA format with triple the circumferential resolution and mean signal intensities were fitted to a 3 parameter saturation recovery curve. Data was presented as median with ranges and analysed using Spearman’s correlation coefficient and Wilcoxon rank sum tests (p<0.05).2, range 80-375 mg/m2). Subjects had normal EDV 67.6 ml/m2 (56-114 ml/ m2), increased ESV 36.3 ml/m2 (23-60 ml/ m2) and normal EF  when compared to normal reported values in children. Ventricular volumes increased with time post chemotherapy  , were studied 10 years 3-12 years) after completing chemotherapy . Ventricular dilatation progresses with time post therapy with larger than average values at approximately 6-7 years from chemotherapy.


Left ventricular noncompaction (LVNC) describes deep trabeculations in the left ventricular (LV) endocardium and a thinned epicardium. LVNC is seen both as a primary cardiomyopathy and as a secondary finding in other syndromes affecting the myocardium such as neuromuscular disorders. The objective of this study is to define the prevalence of LVNC in the Duchenne Muscular Dystrophy (DMD) population and characterize its relationship to global LV function.Cardiac magnetic resonance (CMR) was used to assess ventricular morphology and function in 151 subjects: DMD with ejection fraction (EF) > 55% (n = 66), DMD with EF < 55% (n = 30), primary LVNC (n = 15) and normal controls (n = 40). The non-compacted to compacted (NC/C) ratio was measured in each of the 16 standard myocardial segments. LVNC was defined as a diastolic NC/C ratio > 2.3 for any segment.LVNC criteria were met by 27/96 DMD patients : 11 had an EF > 55% , and 16 had an EF < 55% . The median maximum NC/C ratio was 1.8 for DMD with EF > 55%, 2.46 for DMD with EF < 55%, 1.54 for the normal subjects, and 3.69 for primary LVNC patients. Longitudinal data for 78 of the DMD boys demonstrated a mean rate of change in NC/C ratio per year of +0.36.The high prevalence of LVNC in DMD is associated with decreased LV systolic function that develops over time and may represent muscular degeneration versus compensatory remodeling. Left ventricular noncompaction (LVNC) is characterized by deep trabeculations in the left ventricular (LV) endocardium. The LVNC phenotype has been described in several genetically mediated diseases including the alpha-dystrobrevin mutation, mitochondrial mutations, and Cypher/ZASP mutation ,2. In thPatients with DMD, a lethal X-linked skeletal and cardiac myopathy caused by dystrophin mutations, universally develop cardiac dysfunction . EchocarData was analyzed from records of patients with DMD or LVNC followed at Cincinnati Children’s Hospital Medical Center (IRB). The diagnosis of DMD was confirmed by skeletal muscle biopsy in all patients. The diagnosis of LVNC was made clinically based on accepted non-invasive imaging criteria. All DMD or LVNC patients that underwent CMR between 2005 and 2010 were included. An age-matched control group of subjects with completely normal CMR finding was also analyzed. For patients with more than one CMR study, the most recent study was used for the primary analysis. Serial data was evaluated for all DMD patients with multiple CMR studies. The study was approved by our Institutional Review Board.All CMR studies were performed according to standard clinical protocol. Studies included standard cardiac functional imaging using a retrospective vectorcardiographic (VCG)-gated segmented steady-state free precession (SSFP) sequence. Patients were imaged on both a Siemens Avanto 3 T and GE 1.5 T magnets. A 3 T standard imaging was preceded by frequency scouting and adjustment. Subjects were breath-held as tolerated. For those subjects who could not adequately breath-hold, a free breathing technique with multiple signal averages was used. Standard functional imaging included a short-axis stack of cine SSFP images from cardiac base to apex. The short axis was prescribed as the perpendicular plane to the LV long axis in 2- and 4-chamber views as previously described ,18. TypiVentricular volumes, mass, and global function were assessed via standard planimetry with a semi-automated technique  ,20. ThisThe LVNC status was assessed according to a standard metric previously described . Using aThree of the patients enrolled in the study (1 DMD and 2 primary LVNC) had specimens available for image correlation. The DMD patient underwent placement of a HeartMate left ventricular assist device and both primary LVNC patients underwent orthotopic heart transplantation. An experienced pathologist analyzed the specimens for the presence and extent of LVNC.Prevalence of LVNC was compared using a Chi-Square test and prevalence for each group was estimated using a 95% Wald confidence interval for proportions. Spearman’s Rank correlation was used to determine association between the left ventricular end diastolic volume Z-score and NC/C ratio. Median ratios were compared using the Wilcoxon Rank-Sum test when two groups were present and the Kruskal-Wallis test for more than two. Inter- and intra- observer agreement was measured using the intraclass correlation coefficient (ICC). These values range from 0 to 1, with 0.0-0.2 indicating very little agreement, 0.2-0.4 little agreement, 0.4-0.6 moderate agreement, 0.6-0.8 strong agreement, and 0.8-1.0 very strong agreement. For all tests, a p-value of < 0.05 was considered statistically significant. Corrections for multiple comparisons were made using the Bonferroni method. All analyses were performed using SAS version 9.2 .There were a total of 151 subjects enrolled; DMD (n = 96), normal control (n = 40) and primary LVNC (n = 15). A total of 229 CMR studies were evaluated including 78 serial DMD studies. There were 96 DMD boys: EF > 55% (n = 66) and EF < 55% (n = 30). All 40 normal control subjects had an EF > 55%. Of the 15 patients with primary LVNC, 6 had an EF < 55% and 9 with an EF > 55%. The median ages of the groups are included in Table Among the 96 DMD boys, there were 27 cases meeting the LVNC criterion, with an overall prevalence of 28% . Of the 27 LVNC cases in DMD boys, 11 had an EF > 55%, and 16 with an EF < 55%. The prevalence of LVNC in DMD boys with EF > 55% was 16.7% (95% = 6.8% - 26.6%) compared to 53.3% (95% = 35.4% - 71.2%) for DMD boys with EF < 55% (p = 0.0002). No normal subject had evidence of LVNV or an NC/C ratio > 2.3 in any segment.Particular LV segments that were positive for LVNC with a NC/C ratio > 2.3 were in similar locations in patients with DMD with EF > 55%, DMD with EF < 55% or LVNC. In all the subjects, the apical segments were more likely to have ratios > 2.3 with segment 16 being the most common segment to be positive. Segment 16 was positive in 73% of the primary LVNC patients, 40% of DMD subjects with an EF < 55%, and 9.1% of DMD subjects with an EF > 55%. The segments most commonly positive in the LVNC population were apical segments 13, 15 and 16. In the DMD population, it was segments 11,12 and 16. These segments correspond to the segments that have been described to have scar tissue burden with LGE analysis   for DMD boys with EF > 55% compared to 1.54  for the normal group (p < 0.0001). For DMD boys with EF < 55% median maximal NC/C ratio was 2.46  compared to 3.69  for the LVNC group (p < 0.0001) , the mean number of positive segments was 2.2. This can be compared to the 15 patients with primary LVNC who had a mean of 3.4 positive segments. The median maximal NC/C ratio for all 27 DMD boys that met criteria for LVNC was 3.0 .The presence of LGE was assessed in 90 of the 96 DMD boys. LGE was positive for 30 of these 90 DMD boys. Of the 30 with LGE, 9 (30%) had normal left ventricular function and 21 (70%) had depressed function. There were 12 of 30 (40%) with NC/C ratios greater than 2.3. Eleven of the 12 subjects with both LGE and LVNC had depressed left ventricular function. The segments that were affected for the 30 with LGE were most commonly segments 5, 6, 11, 12, and 16. The most common segments with a NC/C ratio greater than 2.3 were again 11, 12, and 16. In the 12 patients with LGE and LVNC, there were a total of 30 segments with a NC/C greater than 2.3, 22 or 73% of these segments were also positive for LGE. 12 of the 15 patients with primary LVNC had LGE assessed. There was no evidence of LGE in any of these 12 patients. None of the normal patents had evidence of LGE.There was longitudinal data available for 78 of the DMD boys. The median rate of change in NC length per year was +0.92 mm . The median rate of change in C length was −0.36 mm . The median rate of change in NC/C ratio per year was +0.36 . In DMD patients with serial data available, the noncompacted layer increased in thickness as the compacted layer decreased in thickness, leading to an increase in NC/C ratio , myocardial function assessed by CMR strain decreases with age . The LVNAdvanced DMD associated heart disease has also been described to have thinning and fibrofatty replacement of the apical and mid- LV free wall with markedly positive late gadolinium enhancement (LGE) in these segments on CMR ,30. As FThis study is limited by being retrospective. This study is also limited by a lack of universal imaging criteria for the LVNC phenotype. Different criteria for LVNC would yield slightly different prevalence numbers for this population. This group of DMD patients falls in a relatively narrow age range with no patients less than 7 years of age and relatively few older patients.Although these data show that the progression of DMD associated heart disease includes the development of LVNC, these patients likely do not have classic primary LVNC cardiomyopathy. Rather, the changes that occur late in the disease process are characterized by marked alteration in myocardial structure secondary to fibrofatty replacement of myocardial cells and/or a compensatory mechanism due to cardiac dysfunction. This data definitively shows DMD patients that originally had normal NC/C ratios later developed trabeculations as the disease progressed. This may give some insight to the high prevalence of noncompacted tissue of those with cardiac dysfunction. It also raises the broader question of whether LVNC in patients with LVNC cardiomyopathy and dilated ventricles is a primary or secondary process.LVNC: Left ventricular non-compaction; LV: Left ventricular; EF: Ejection fraction; DMD: Duchenne muscular dystrophy; CMR: Cardiac magnetic resonance imaging; NC: Non-compacted; C: Compacted; LGE: Late gadolinium enhancement; NC/C: Non-compacted to compacted ratio; IQR: Interquartile range.There are no competing interests for any of the authors to disclose.CS conceived of the study, and participated in its design and coordination, carried out all data collection and helped to draft the manuscript. MT participated in the design and coordination of the study and helped to draft the manuscript. WM participated in the design and coordination of the study and helped to draft the manuscript. LC helped with study design. EK provided statistical support. JP provided statistical analysis. DWB helped with design of the study and helped to draft the manuscript. KH conceived of the study, and participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.


Thalassaemia major (TM) affects hundreds of thousands of patients worldwide but only a minority have access to regular blood transfusion and chelation therapy. Cardiovascular magnetic resonance (CMR) T2* measurement provides an accurate, reproducible measurement of cardiac iron which is the cause of heart failure and early death in many transfused TM patients. This technique has been adopted as part of routine management in many countries where survival is now approaching normal but little is known about the severity and effects of myocardial iron loading in different geographical regions.The aim of this study was to describe the burden of disease of myocardial siderosis (measured by T2*) in different populations throughout the world and to assess the relationship between T2* and outcome such as heart failure and cardiac death.34 worldwide centres were involved in this survey of 3376 patients from Europe, the Middle East, North America, South America, North Africa, Australia and Asia. Anonymised data on myocardial T2* values were analysed in conjunction with clinical outcomes (heart failure and death).Overall, 57.5% of patients had no significant iron loading (T2* >20ms), 22.6% had moderate cardiac iron (10ms<T2*≤20ms) and 19.9% had severe cardiac iron (T2* ≤10ms) at baseline. The lowest burden of iron was found in North Africa, North and South America with an intermediate level in Australia, Europe and the Middle East but a high proportion of patients (>50%) in South-East Asia had cardiac iron (T2* >20ms) at baseline. At the time of the first scan, 100 patients (3.3%) had confirmed heart failure, the majority of whom (77.0%) had myocardial T2* <10ms with almost all (99%) having T2* <20ms. There were 113 patients who subsequently developed heart failure. 92.0% of these had T2* <10ms and 99.1% had a T2* <20ms. There were 39 deaths. Cardiac T2* values were <10ms in 79.5%, with 92.3% <20ms.Even in this well-treated cohort with access to transfusion, chelation and CMR, there is a large proportion of TM patients with moderate to severe cardiac iron loading. Low T2* (<10ms) is associated with cardiac failure and death. There is a huge unmet worldwide need in terms of access to specialist medical care (including transfusion and chelation therapy) together with advanced monitoring techniques (such as CMR).


Sodium channel blockers augment ST-segment elevation in the right precordial leads in patients undergoing Brugada-type electrocardiography (ECG). However, their effect on echocardiographic features is not known. We address this by assessing global and regional ventricular function using conventional Doppler and two- dimensional (2D) speckle tracking techniques.Thirty-one patients with Brugada-type ECG were studied. A pure sodium channel blocker, pilsicainide, was used to provoke an ECG response. The percentage longitudinal systolic myocardial strain at the base of both the right ventricular (RV) free wall and the interventricular septum wall was measured using 2D speckle tracking. Left ventricular (LV) and RV myocardial performance (TEI) indices were also measured.P < 0.01), and both RV and LV TEI indices increased  after pilsicainide administration.The pilsicainide challenge provoked a positive ECG response in 13 patients (inducible group). In the inducible group, longitudinal strain was significantly reduced only at the RV (-27.3 ± 5.4% vs -22.1 ± 3.6%, Temporal and spatial analysis using the TEI index and 2D strain imaging revealed the deterioration of global ventricular function associated with conduction disturbance and RV regional function in patients with Brugada-type ECG and coved type ST elevation due to administration of a sodium channel blocker. Brugada syndrome is characterized by ST-segment elevation in right precordial leads and electrolyte disturbances associated with a high risk of cardiac sudden death . DespiteRecently, two-dimensional (2D) strain imaging, based on a speckle tracking technique, has been introduced to evaluate regional myocardial function without angle dependency . MoreoveWe aim to evaluate the echocardiographic characteristics in patients with Brugada-like ECG using 2D strain imaging and the TEI index, and to clarify whether or not changes in these indices occur according to the ECG response to a sodium channel blocker.We studied 31 patients with normal LV function evaluated by 2D echocardiography with no evidence of typical Brugada signs on their baseline ECG during hospitalization. We enrolled the symptomatic patients who had a history of documented arrhythmias other than ventricular tachycardia or ventricular fibrillation or episodes related to syncope or fainting, but no documented arrhythmias at that time, and the asymptomatic patients with documented ECG abnormalities suspected of being Brugada-type or like Brugada-type abnormalities. Their ECG was either type 2, i.e. showing ST-segment elevation (saddleback type) displaying J wave amplitude or ST-segment elevation of ≥ 2 mm in more than one right precordial lead under baseline conditions, or type 3, i.e. showing right precordial ST-segment elevation of < 1 mm of the saddleback type, according to the Heart Rhythm Society and the European Heart Rhythm Association [Pilsicainide was infused intravenously (1 mg/kg in 10 minutes) to provoke an ECG response. Drug administration was immediately stopped when ST elevation (> 0.5 mV), extensive QRS prolongation, unfavorable symptoms and frequent ventricular arrhythmias were observed. No complications resulted from these investigations. A positive ECG response was defined as a > 200 mcV elevation of the J wave amplitude in more than one right precordial lead [Group 1: non-inducible (n = 18); pilsicainide challenge did not provoke ECG changesGroup 2: inducible (n = 13); pilsicainide challenge provoked coved type ST elevation.Patients with atrial fibrillation, a history of significant coronary heart disease, valvular heart disease, cardiomyopathy, a history of cardiac operation, or abnormal LV systolic function were excluded from the study. The protocol was approved by the Institutional Clinical Research and Ethics Committee of the Yamaguchi University Hospital. Written informed consent was obtained from all participants before the study.(a-b)/b, where a is the interval between cessation and onset of transmitral (or transtricuspid) flow and b is the aortic (or pulmonary) flow ejection time, were also measured by pulsed-Doppler echocardiography. The peak velocities of early (E) and late (A) mitral inflow and the deceleration time of the E wave (DcT) were measured using pulse-wave Doppler. The isovolumic contraction time (ICT) was measured as the time interval from the cessation of LV inflow to the onset of LV outflow velocity.Echocardiography was performed with the patient in the left lateral decubitus position at end-expiration using a GE-Vingmed Vivid 7 system  equipped with a 2-4 MHz sector transducer. Images were recorded at baseline conditions and after pilsicainide. LV end-diastolic and end-systolic dimensions were measured in the parasternal long-axis view. The LV ejection fraction was obtained using the biplane Simpson method from the apical four- and two-chamber views. Both LV and RV inflow velocities were obtained from the four- chamber view with the pulsed wave Doppler sample volume positioned at the tips of the mitral and tricuspid leaflets during diastole. The LV outflow velocity was obtained from the LV apical long-axis view with the Doppler sample volume placed below the aortic valve. The RV outflow velocity was obtained from the parasternal short-axis view at the aortic valve level with the Doppler sample volume placed below the pulmonic valve. These velocity patterns were digitized and stored in a hard disk on the ultrasound machine for 5 cardiac cycles for further analysis. Both LV and RV TEI indexes, as LV apical four-chamber views were acquired using second harmonic gray scale imaging. Three consecutive cardiac cycles were acquired at end-expiratory apnea, and digitally stored in a hard disk for offline analysis. The images were processed on a workstation using EchoPAC Q  analysis software. The 2D strain echocardiography used serial gray -scale sector images based on frame-by- frame tracking of small rectangular image blocks with stable speckle patterns . The geot test. P values less than 0.05 were considered significant.Values were expressed as means ± SD. Data were analyzed using analysis of variance to compare group differences followed by Scheffe's multiple comparison test. Group differences after pilsicainide were analyzed using the 2-tailed Student's A total of 15 studies were randomly selected for the reanalysis of 2D strain data. The measurements were repeated after 1week by same echocardiographer to assess intraobserver reproducibility. Interobserver reproducibility was assessed by a second observer who was blind to the first observer's measurements. Intraobserver and interobserver reproducibility were analyzed using both Pearson's bivariate two-tailed correlations and Bland-Altman analysis (with 95% agreement limits).The baseline characteristics are summarized in Table Both RV- and LV-TEI indices at baseline were similar in the 2 groups. After pilsicainide infusion, both RV- and LV- TEI indices increased in the inducible groups. However, in the non-inducible group, the RV- and LV-TEI indices did not change.P < 0.01)  and r = 0.86 (P < 0.001), respectively. The limits of agreement for intraobserver reproducibility were -6.0% to 5.0% in the RV free wall and -3.3% to 2.8% in IVS. For interobserver reproducibility, Pearson's correlations at the base of the RV free wall and the IVS were r = 0.86 (P < 0.001) and r = 0.81 (P < 0.001), respectively. The limits of agreement for intraobserver reproducibility were -3.2% to 8.7% in the RV free wall and -2.1% to 3.3% in the IVS.In this study, we observed the reduction of longitudinal strain of basal segment of RV by 2D speckle tracking techniques in patients with Brugada-type ECG and a positive response to pilsicainide.Brugada syndrome is characterized as ST-segment elevation from a depressed RV epicardial action potential dome or a RV subepicardial action potential shortening ,12. ThusAlthough previous studies reported a delay in the timing of the onset of RV contraction using tissue Doppler imaging in type 1 Brugada patients, regional RV or LV function in such situations was not fully evaluated ,14. In tBoth the RV and LV TEI indices deteriorated in the inducible group; however, these indices did not deteriorate in the non-inducible group. Although previous study showed that the RV ejection time shortened as the Brugada ECG pattern emerged after flecainide infusion , we did A previous study reported that sodium channel blocker administration resulted in ST-segment elevation and RBBB in a patient with an SCN5A mutation . We did Although conventional echocardiography failed to detect structural abnormalities in patients with Brugada-type ECG and coved type ST elevation induced by a sodium channel blocker, temporal and spatial analysis by TEI index and 2D strain imaging revealed the deterioration of global ventricular function associated with the manifestation of conduction disturbance and the reduction of RV regional function.RV: right ventricle/ventricular; LV: left ventricle/ventricular; 2D: two-dimensional; TEI index: myocardial performance index; TDI: tissue Doppler imaging; ICT: isovolumic contraction time.The authors declare that they have no competing interests.KM conceived the study, participated in the study, performed echocardiographic studies and drafted the manuscript. TU participated in the study design of study. TT and YN participated in the study and performed echocardiographic studies. YW performed echocardiographic and statistical analyses. MM participated in echocardiographic studies and in the study design. All authors have read and approved the final manuscript.


Objective. Ceruloplasmin was elevated in patients with coronary heart disease, but the relationship between ceruloplasmin and heart failure was still unknown. We aimed to evaluate ceruloplasmin in heart failure patients and assess association between ceruloplasmin and the extent of heart failure. Methods and Results. 202 heart failure patients were divided into ischemic (78 with coronary stenosis) and nonischemic groups (124 without coronary stenosis). 94 subjects without heart failure were included as controls. The extent of heart failure was defined according to NYHA classification. Ceruloplasmin levels in ischemic (P < 0.001) and nonischemic groups (P < 0.001) were higher than those in control group. Ceruloplasmin had a positive linear correlation with C-reactive protein (P < 0.01) and a negative linear correlation with LVEF (P < 0.05). In nonischemic group, CP levels were significantly different among different NYHA subgroups (P < 0.05). The correlation between ceruloplasmin and extent of heart failure was calculated by binary logistic regression. Ceruloplasmin showed an independent association with the extent of heart failure in nonischemic cardiomyopathy patients (P < 0.05). Conclusions. Ceruloplasmin was significantly elevated in patients with ischemic or nonischemic cardiomyopathy and had linear correlation with C-reactive protein and LVEF. In nonischemic cardiomyopathy patients, the ceruloplasmin value was an independent biomarker associated with the extent of heart failure. During the progression of cardiomyopathy, heart failure was gradually aggravated and became the major cause of unplanned hospitalization. The mortality of heart failure is still high in the present therapy, and brain natriuretic peptide, which is elevated in acute heart failure, could be false positive in pulmonary disease, like pulmonary embolism or chronic obstructive pulmonary disease.Metal metabolism, metalloenzymes, and their activities of oxidation and inflammation are involved in progression of heart failure . Many stOur study aimed to evaluate the predictive value of serum ceruloplasmin in patients with ischemic and nonischemic cardiomyopathies, and assess the association between CP levels and the extent of heart failure, CP levels and other parameters in both ischemic and nonischemic cardiomyopathy patients.Between December 2009 and April 2011, a total of 202 patients were recruited consecutively from those who were admitted and diagnosed as heart failure patients according to New York Heart Association (NYHA) classification at the Department of Cardiology, Second Affiliated Hospital of Zhejiang University College of Medicine. Patients with advanced renal disease , noncardiac acute inflammatory states, known malignancies, or liver dysfunction resulting from organic hepatic diseases were excluded. However, patients with diabetes mellitus, hypercholesterolemia, hypertension, and transient liver dysfunction induced by circulatory congestion in congestive heart failure were enrolled in the study. Patients who had coronary stenosis findings in coronary angiography belonged to ischemic cardiomyopathy group, and the other patients belonged to nonischemic cardiomyopathy group. 94 subjects without organic heart disease were included in the control group. Other risk factors were balanced among three groups. The extent of heart failure is defined according to the NYHA functional classification system: NYHA I —no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea; NYHA II (mild)—slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea; NYHA III (moderate)—marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea; NHYA IV (severe)—unable to carry out any physical activity without discomfort. Symptoms of heart failure are present at rest. If any physical activity is undertaken, discomfort increases.All patients enrolled in the study were given informed consent, and the hospital ethics committee approved the study protocol.β-blocker, calcium channel blocker, aspirin/clopidogrel, and statin) were also collected. BMI (body mass index) is defined as the individual's weight (kg) divided by square of height (m).For each patient, the clinical characteristics were collected, including age, gender, height, weight, history of hypertension, diabetes mellitus, cigarette smoking, and NYHA classification. Medications taken —left-ventricular ejection fraction, LVIDd (cm)—left-ventricular internal diameter at end diastole, and LA (cm)—left atrium.Blood samples were collected on admission, using pyrogen-free tubes containing EDTA for plasma test and sterile tubes containing gel for serum separation  and then immediately centrifuged at 4000 rpm for 10 min at 4°C. All the samples were analyzed in laboratory of Second Affiliated Hospital of Zhejiang University College of Medicine. The results of blood biochemical test including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, creatinine, C-reactive protein, troponin I, creatine kinase-MB, and CP were collected and analyzed.The levels of serum ceruloplasmin were measured by nephelometry  . The ceruloplasmin also had a negative linear correlation with LVEF (P < 0.05).To assess the relationship between ceruloplasmin and other parameters, the Pearson linear correlation was evaluated in all the subjects in P < 0.001) and nonischemic cardiomyopathy groups (P < 0.001) were higher than those in the control group (P > 0.05) (P < 0.05)  . In noni < 0.05) .χ2 = 4.489, odds ratio (OR) = 1.010, 95% confidence interval (CI): 1.001–1.019, P = 0.034) and age (P = 0.046) were correlated with the extent of heart failure. The correlation between the CP levels and the extent of heart failure was independent of gender, smoking, alcohol taking, hypertension, diabetes mellitus, AST, uric acid, CKMB, CRP, LVEF, and other parameters  is a 132-kDa plasma glycoprotein which binds 95% of the total circulating copper in healthy adults . The livDuring the progression of heart failure, the inflammatory and oxidative reactions were activated and enhanced as a protective mechanism. So we hypothesized that CP, which was an index of the metal metabolism, still could be the inflammatory and oxidative biomarker in heart failure. The results proved our hypothesis. The CP level was elevated in patients with cardiomyopathy and showed the positive linear correlation with uric acid and C-reactive protein and negative linear correlation with left-ventricular ejection fraction, which meant that CP was increased with other acute-phase biomarkers when heart function got worse. Then we compared the CP levels of different NYHA levels in ischemic and nonischemic cardiomyopathy groups, respectively.In ischemic heart disease, ischemic injury to cardiac muscle induced the inflammation and redox toxic reactions and the injury ran through every stage of ischemic cardiomyopathy. Copper might be involved in the redox toxic reaction . CP is eIn nonischemic cardiomyopathy patients, heart failure is always accompanied with tissue hypoxia. The hypoxia was exacerbated with low-pulse oxygen saturation clinically when heart failure was aggravated. CP synthesis was increased as a defense mechanism in response to hypoxia . Our resWe concluded that CP levels were significantly high in patients with ischemic or nonischemic cardiomyopathy and had a positive linear correlation with C-reactive protein and a negative linear correlation with LVEF. In nonischemic cardiomyopathy patients, the CP value was an independent biomarker associated with the extent of heart failure. Further studies should be applied to confirm our data in a larger number of patients and to clarify the mechanism.