In right ventricular failure (RVF), an interatrial shunt can relieve symptoms of severe pulmonary hypertension by reducing right ventricular preload and increasing systemic flow. Using a pig model to determine if a pulmonary artery - left atrium shunt (PA-LA) is better than a right atrial - left atrial shunt (RA-LA), we compared the hemodynamic effects and blood gases between the two shunts.Thirty, male Large White pigs weighting in average 21.3 kg ± 0.7 (SEM) were divided into two groups (15 pigs per group): In group 1, banding of the pulmonary artery and a pulmonary artery to left atrium shunt with an 8 mm graft (PA-LA) was performed and in group 2 banding of the pulmonary artery and right atrial to left atrial shunt (RA-LA) with a similar graft was performed. Hemodynamic parameters and blood gases were measured from all cardiac chambers in 10 and 20 minutes, half and one hour interval from the baseline (30 min from the banding). Cardiac output and flow of at the left anterior descending artery was also monitored.In both groups, a stable RVF was generated. The PA-LA shunt compared to the RA-LA shunt has better hemodynamic performance concerning the decreased right ventricle afterload, the 4 fold higher mean pressure of the shunt, the better flow in left anterior descending artery and the decreased systemic vascular resistance. Favorable to the PA-LA shunt is also the tendency - although not statistically significant - in relation to central venous pressure, left atrial filling and cardiac output.The PA-LA shunt can effectively reverse the catastrophic effects of acute RVF offering better hemodynamic characteristics than an interatrial shunt. Pulmonary hypertension and right ventricular dysfunction are associated with poor survival. Management of patients with acute decompensate RV failure is largely empiric and targeted towards treating underlying precipitants while optimizing conditions of RV preload, afterload and contractility.However, right-sided heart failure remains a major problem in the long-term follow-up, leading to impairment of functional status, severe arrhythmia, and premature death. Treatment consists of pulmonary vasodilator therapy, long-term oxygen therapy, anticoagulation, and lung transplantation, or, at times, heart-lung transplantation. Management strategies for patients who develop acute refractory right ventricular failure are:1. Mechanical support to the failing right ventricle,2. Conventional pulmonary vasodilators,3. Cavopulmonary diversion in select cases, and4. Maintenance of an adequate left ventricular performance throughout the recovery period .In recent years, percutaneous balloon atrial septostomy (BAS) has been established as a palliative treatment or bridge to transplantation in patients with severe right-heart failure refractory to conventional therapy -5. BAS aThe animal research protocol was approved by the local authorities (A.Π. 3940/6-10-2008) in Athens. All animals used in this study were treated according to the "Guide for the care and use of Laboratory animals" published by the US National Institutes of Health .Thirty pigs weighing 22 to 35 kg were premedicated with ketamine hydrochloride (15 mg/kg IM) and midazolam (0.5 mg/kg IM), anesthetized with thiopental sodium (9 mg/kg IV bolus) and fentanyl citrate (0.5 mg IV bolus), followed by continuous IV infusions of thiopental sodium (1 mg/min), fentanyl citrate (4 mg/min), pancuronium bromide (0.25 mg/min), and lidocaine (2 mg/min), throughout the experiment. After intubation (8Ch), respiration was controlled with a Soxitronic volume respirator , supplying oxygen at 100%. No changes of tidal volume, respiratory rate, and percentage of inspired oxygen were made.The chest was opened via a midline sternotomy, and the heart was suspended in a pericardial cradle. Catheters were placed, in the right atrium via the right external jugular vein which was surgically dissected; a right side arterial line was inserted under direct vision by a small incision in the groin, and in the left atrium directly through the left atrial appendix. To the arterial line was connected a FloTrac sensor also,  to measures parameters such as CCO, SVV/SV, SVR. This sensor is achieving measurements by pulse contour analysis based on arterial pressure waveform. In this way it is possible to avoid the use of Swan Ganz and consequently interactions with tricuspid valve function. The proximal to mid left anterior descending (LAD) coronary artery was dissected free and, a transit time flow-meter probe, (Transonic Inc. Ithaca New York 400-Series Multichannel Flowmeter) was applied. The temperature of the animal was kept within 0.5°C of the baseline value with a heating blanket and lamp. ECG, for severe rhythm disturbances, arterial pressure, central venous pressure, pulmonary artery pressure and left atrial pressure were continuously monitored. Fluid (Ringers lactate) was given at a rate of 20 ml/kg.To achieve RVF a banding of the very distal main pulmonary artery was performed. For banding we used a vessel loop (nylon tape) with a snare Figure . The banAll measurements were taken at end expiration with the ventilator turned off. Pulmonary artery band tightness was adjusted so as not to allow the systolic arterial blood pressure to fall below 60 mmHg at anytime during the experiment. With the beginning of the shunt surgery, the animals were systemically heparinized (100U/kg).Two different settings of shunts were evaluated. Group (1) PA-LA shunt (n 15) and group 2) RA-LA shunt (n 15). A right atrial to the left atrial shunt was created with an interposition of an 8 mm PTFE graft in group No 2  or median  for continuous variables and as percentages for categorical data. The Kolmogorov - Smirnov test was utilized for normality analysis of the parameters. The comparison of variables at each time point was performed using the Independent samples t-test or the Mann-Whitney test in case of violation of normality. One factor Repeated Measures ANOVA model was used for the comparison of different time measurement of variables for each group. Pair wise multiple comparisons were performed using the method of Tukey critical difference.To indicate the trend in the first 20 minutes of intervention, the median percentage changes after 10 and 20 minutes respectively are calculated. Comparison of percentage change from baseline of parameters during the observation period between two groups was analyzed using the Mann-Whitney test because of violation of normality.All tests are two-sided, statistical significance was set at p < 0.05. All analyses were carried out using the statistical package SPSS ver. 16.00 .The central venous pressure (mean), the mean pressure of left atrium, the cardiac output, the pressure of the distal portion of pulmonary artery at baseline and during 10 and 20 minutes interval were similar in both groups . Pairwise comparisons show statistically significant difference between all time measurements. The heart rate variable at baseline was 95.5 ± 10.45 pulses/min, at 10 minutes interval with PA - LA shunt was 112.80 ± 9.71 pulses/min and at 20 minutes interval 105.20 ± 16.90 pulses/min, whereas with the RA - LA shunt the measurements of heart rate variable at 10 and 20 minutes interval were 106.87 ± 18.31 pulses/min and 103.80 ± 13.52 pulses/min.There is statistically significant difference among the time measurements of mean arterial blood pressure variable for the PA - LA shunt, in comparison with the RA - LA shunt between al time measurements (p < 0.005). The mean blood pressure variable at baseline was 64.67 ± 6.72 mmHg, at 10 minutes interval with PA - LA shunt decreased at a variable of 59.33 ± 14.02 mmHg and at 20 minutes interval at 49.87 ± 10.08 mmHg, whereas with the RA - LA shunt the measurements of mean blood pressure variable at 10 and 20 minutes interval were 59.20 ± 10.71 mmHg and 58.60 ± 13.43 mmHg. Between the two groups (PA - LA shunt and RA - LA shunt) there is statistically significant difference of mean blood pressure variable at 20 min interval  with the mean blood pressure of PA - LA shunt at the level of 49.87 ± 10.08 mmHg and of RA - LA shunt at the level of 58.60 ± 13.43.As for the mean right ventricular pressure (RVP) variable, there is statistically significant difference among the time measurements of the RVP variable for the shunt PA-LΑ (p < 0.005). Pairwise comparisons show statistically significant difference between all time measurements. Also, between the two groups at 10 minute interval, a significant statistically difference (p < 0.022) is observed with the measurements to be 15.93 ± 4.73 mmHg for the shunt PA-LΑ and 10.87 ± 3.60 mmHg for the shunt RA-LΑ. Concerning the percentage change from baseline to 10 min of the mean right ventricular pressure variable, there is statistical significant difference between the two groups (p < 0.074), with 50% decrease at the PA-LA shunt and 64% decrease at the RA-LA shunt.The variable of shunt pressure has statistically difference between the two groups at 10 minute and 20 minute interval (p < 0.005), whereas there is a significant statistically difference between groups concerning the percentage change from baseline to 20 min (p = 0.023). Comparison between all time measurements of proximal pulmonary artery pressure for both groups reveals a statistically difference (p < 0.005).The observed decrease of SVR has a statistically difference among the 20 minute interval measurements for the shunt PA-LΑ and for the RA-LA shunt (p < 0.005). Also there is statistically difference of SVR variable between the two groups at 20 minute interval (p = 0.075) and there is statistical significant difference between the two groups concerning the percentage change from baseline to 20 minutes of the SVR variable (p = 0.021).Another important variable that was measured was the flow at the LAD. Measurements revealed statistically significant difference among the time measurements of the LAD flow variable for the shunt RA-LΑ (p < 0.005) at 20 minute interval, with a 33.3% decrease. Between the two groups, at 20 minutes interval, the observed difference is statistically significant (p < 0.005). Finally, the observed LAD flow variable between the two groups at 20 minutes has a significant statistically difference (p < 0.005).2 and arterial pO2, arterial O2% saturation, pulmonary artery pH, pCO2 of pulmonary artery and O2% saturation of left atrium . Pairwise comparisons show statistically significant difference between all time measurements. The same observations are made for the decrease of O2% saturation of the pulmonary artery.The decrease of pO2 of the left atrium increase is statistically significant between the two groups at 10 minute interval (p = 0.052) and at 20 minute interval (p = 0.058). Τhere is also a statistical significant difference between groups concerning the percentage change from baseline to 10 minute of the pCO2 of the left atrium variable (p = 0.016) and the percentage change from baseline to 20 minute of the pCO2 of the left atrium variable (p = 0.023).pCO2 of the left atrium decrease reveals a statistically significant difference among the time measurements for the shunt PA-LΑ (p < 0.005) and RA-LA shunt. Pairwise comparisons show statistically significant difference between all time measurements. At 10 minute interval, between the two groups there is a statistically difference (p = 0.015), and concerning the percentage change from baseline to 10 minute, the difference between the two groups is statistical significant (p = 0.05).Least, the pO2, pCO2 and left atrial pO2, pCO2 can be interpreted as a technical error or as a condition error, probably because of contiguity of the sample collector to the graft.It is anticipated that the minor fall of PO2 and the minor increase of PCO2 will not influence saturation because of the morphology of the oxygen-hemoglobulin dissociation curve. The discrepancy between arterial pORight ventricular function is identified to be an independent risk factor for mortality in various diseases as chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH) , adult respiratory distress syndrome (ARDS), etc . Also puOften the development of a RVF exhibits the final phase of the disease. In cardiothoracic surgery, RVF seems to be a frequent cause for postoperative cardiogenic shock associated with high mortality -13. DiffThe first idea of a pulmonary artery to left atrium shunt was introduced 50 years ago, and belongs to Bilgutay and Lillehei . Gupta eBesides several other mechanisms which lead to low cardiac output in RVF, a major feature is a reduced trans-pulmonary blood flow with a reduced left atrial respectively ventricular filling result, which is called serial ventricular interdependence. Our aim was to evaluate hemodynamic status of a pulmonary artery to left atrium shunt which can have many advantages and comparison of this shunt with an interatrial shunt.Pulmonary artery banding in pigs reproducibly results in right side circulatory failure detectable as an increase in right ventricular and mean pulmonary artery pressures and a decrease in left ventricular end-diastolic pressure. In our study, in both groups after shunting it was detectable an increase in heart rate at 10 and 20 minute and a decrease of mean arterial pressure but there was statistically significant difference of mean arterial pressure between the two groups at 20 minute (p = 0.054) being more prominent in group 1 (PA-LA) shunt. This result can be explained from the concomitant decrease in this group of SVR at 20 minutes. Τhere is statistical significant difference between groups concerning the percentage change from baseline to 10 minute of the SVR variable and a statistically significant difference between the two groups at 20 minute (p = 0.075). Our recordings of a low MAP and low SVR in both groups are consistent with the results described by other investigators .The right ventricular pressure was statistically significant higher in the group of RA-LA. Right ventricular overload - pressure lead often to life threatening ventricular tachycardias. From this point of view the PA-LA shunt has a significant advantage. We observed that right atrial pressure in both groups was not increased as expected, because the experiment was acute and the tricuspid valve by epicardial echocardiography had sufficient competence. However, an interatrial shunt is likely beneficial only if sufficient right-to-left shunting occurs to increase cardiac output.The results of lower mean arterial pressure and SVR in favor of PA-LA shunt insinuate easier manipulation of heart function in order to optimize heart performance by simple maneuvers like volume infusion or medical intervention in cases of real conditions of right ventricle overload.Atrial septostomy has been associated with a risk of intraprocedural and postprocedural mortality up to 30% in several series ,23-25, mAccording the Hagen-Poiseuille lawQ: volumetric flow rate, π: mathematical constant, η: dynamic fluid viscosity [pascal - second (Pa·s)], Pi: inlet pressure, Po: outlet pressure, L: total length of the tube in the x direction (meters), R: is the radius.the PA - LA shunt has 10 fold higher volumetric flow rate, where Because of the anatomical contiguity between pulmonary artery and left atrium, the length of the PA-LA graft is always shorter than the RA-LA graft. The pressure gradient PA-LA is always higher than the RA-LA. These two issues constitute an inherent advantage of PA-LA shunt and are rendering PA-LA shunt more effectively in that it can provide wider range of achievable flows through the shunt. Given the fact that the current technology allows the pulmonary artery banding to be adjustable, we can assume that in the future we may be able to calculate the ideal flow in an individualized manner.To our surprise, systemic arterial de-saturation following the PA-LA shunt was not increased dramatically with devastating consequences such as systemic oxygen delivery. The advantages of a pulmonary artery to left atrium shunt are the following:1. Can be performed without extracorporeal circulation2. Can be used with a telemetrically controlled adjustable occlusion device, as the Flo-Watch pulmonary artery banding device , which has been successfully introduced in clinical practice of banding .3. Can be easily occluded with the current devices, as the Gianturco-Grifka vascular occlusion device which is an appropriate closure system to occlude the shunt because of the large size (9 mm) 4. Can be easily performed in conjunction with a pumpless lung assist device as Novalung in parallel with the PA shunt or in a serial setting .Our experiments have showed that a PA-LA shunt can more effectively moderate or even partially reverse the adverse effects of acute right ventricle pressure overload than an interatrial shunt, offering a decrease in right ventricle afterload, increased flow in left anterior descending artery with less mean arterial pressure and lower SVR.Our study has some limitations. First of all, all measurements were performed in open chest surgery. Secondly, the ventilation supplying oxygen was at 100% and not at room air oxygen. Finally the measurements were taken at 10 and 20 minute interval. The above parameters may alter the results of blood gases. Nevertheless all measurements taken together allow for a realistic evaluation of the overall picture. The use of other acute RVF models and the determination of long term results are a matter of further investigations.RV: Right Ventricle; RA: Right Atrium; RVF: Right ventricular failure; RVO: Right ventricular overload; PA-LA: pulmonary artery to left atrium shunt; RA-LA: Right atrium to left atrium shunt; LAD: left anterior descending artery; CCO: Continuous Cardiac Output; SV: Stroke Volume; SVV: Stroke Volume Variation; SVR: Systemic Vascular Resistance; COPD: chronic obstructive pulmonary disease; PAH: pulmonary arterial hypertension; ARDS: adult respiratory distress syndrome; ECG: Electrocardiogram; RVP: Right Ventricular Pressure.The authors declare that they have no competing interests.All authors read and approved the final manuscript.MA and TS performed all the experiments, collected the data and drafted the manuscript.AP is the clinical director of the experimental laboratory, helped out with the experiments and the data collection.DM revised it critically for important intellectual contentVD revised it critically for important intellectual contentGB have given final approval of the version to be published


To analyze left ventricular (LV) remodeling using an accurate 3D evaluation of afterload-related changes in LV geometry.To maintain an effective LV-arterial coupling the LV adapts to the increased afterload caused by aging or cardiovascular disease. However, subsequent changes in LV mass and concentric remodeling have been associated with poor outcome. To understand LV remodeling, we studied variations of 3D myocardial wall stress (MWS), its geometrical factor as well as diastolic LV mass to volume ratio (LVM/EDV) on a population with a wide range of afterload.2). All subjects had short axis cine CMR acquisitions (GE 1.5T) followed by carotid applanation tonometry calibrated using brachial pressures recorded during CMR. After myocardial delineation, the LV geometrical factor LVGF, previously described by Grossman, was calculated as a combination of the local LV radius and myocardial thickness while considering the LV longitudinal curvature to correct for partial volume effects, especially in apical slices. This LVGF was combined with peak systolic pressures (PSP) resulting in MWS. For AVS patients, the echocardiographic transaortic valve maximal gradient was added to the tonometric PSP.Indeed, we studied 57 patients divided into three subgroups: 1) C1 included 22 healthy subjects aged between 22 and 37 years (26±5 years), (2) C2 included 23 healthy subjects aged between 41 et 81 years (55±9 years) and 3) AVS included 12 subjects (75±14 years) with aortic valve stenosis (AVS) characterized by  while LVM/EDV  was increased in AVS significantly but failed to discriminate between age groups without AVS. Gradual changes in LV geometry reflected by the 3D LVGF demonstrated the ability of the LV to adapt to the increased afterload and therefore to maintain constant MWS. Indeed, no significant variations in MWS were found between the three subgroups Ejection fraction was homogeneous between the three subgroups  The significant and gradual elevation in PSP found between the three groups  caused changes in LV geometry (figure The described 3D evaluation of LV geometry, which can be easily integrated to standard CMR LV function evaluation since it only requires routine myocardial delineation in systole, sensitively characterized LV remodeling related to aging or to AVS.


We sought to determine the feasibility and reproducibility of cardiac magnetic resonance (CMR) myocardial feature tracking (FT) for quantitative wall motion assessment during intermediate dose dobutamine stress magnetic resonance (DSMR) imaging.DSMR imaging is an established tool to assess hibernating myocardium and ischemia. Analysis is typically based on visual assessment with considerable operator dependency. CMR-FT is a recently introduced technique for tissue voxel motion tracking on standard steady-state free precession (SSFP) images to derive circumferential and radial myocardial mechanics.10 healthy subjects were studied at 1.5 Tesla. Myocardial strain parameters were derived from SSFP cine images using dedicated CMR-FT software . Right ventricular (RV) and left ventricular (LV) longitudinal strain (EllRV and EllLV) and LV long-axis radial strain (ErrLAX) were derived from a 4-chamber view at rest. LV short-axis circumferential strain (EccSAX) and ErrSAX, LV ejection fraction (EF) and volumes were analyzed at rest and during dobutamine stress (10 and 20 μg * kg-1* min-1).In all volunteers strain parameters could be derived from the SSFP images at rest and stress. EccSAX values showed significantly increased contraction with DSMR . ErrSAX increased significantly with dobutamine . In parallel with these changes, EF increased significantly with dobutamine . Observer variability was best for LV circumferential strain (EccSAX ) and worst for RV longitudinal strain (EllRV) as determined by 95% confidence intervals of the difference.CMR-FT reliably detects quantitative wall motion and strain derived from SSFP cine imaging that corresponds to inotropic stimulation. The current implementation may need improvement to reduce observer-induced variance. Within a given CMR lab, this novel technique holds promise of easy and fast quantification of wall mechanics and strain.AS receives grant support from the British Heart Foundation (BHF) (RE/08/003 and FS/10/029/28253) and the Biomedical Research Centre (BRC-CTF 196). SK receives grant support from the American College of Cardiology Foundation, the Edna Ittner Pediatric Foundation, and the Children’s Hospital and Medical Center Foundation.


Atrial fibrillation (AF) is a common sustained cardiac arrhythmia associated with increased risks of heart failure, left ventricle (LV) dysfunction, and known to cause an increase in left atrium (LA) volume with decrease in atrial contractility. Cine magnetic resonance images (MRI) were used to measure changes in LA and LV function in a chronic AF goat model. Ejection fraction (EF), end diastolic volume (EDV), end systolic volume (ESV), and stroke volume (SV) measurements of both the LV and LA were made from cine-MR images to track the progression of disease in goats that were induced with AF using neurostimulators.AF was induced in 7 goats with rapid atrial pacing. A neurostimulator  was implanted in the neck and delivered 50 Hz stimulation every other second at 2-3 times diastolic threshold. Prior to MRI, the device was turned off and goats that were in arrhythmia, were cardioverted to sinus rhythm with a t-wave synchronized DC shock. After MRI, the neurostimulators were turned back on. All animals underwent imaging at baseline (before device implantation) and every month afterward. Cine-MRI was performed in the short-axis view for LV evaluation and in trans-axial plane for LA evaluation. Images were acquired on a 3T Trio scanner . A 2D FLASH sequence was used in each orientation with TR/TE=3.3/1.54 ms; in-plane resolution=1.25 x 1.25 mm, slice thickness = 6 mm; flip angle=20 degrees; bandwidth = 790 Hz/pixel and zero spacing between the slices. Segmentations of the LV and LA . Significant increase in LA volume was also observed following atrial pacing. Atrial pacing affects the volumes of both atrium and ventricle resulting in statistically significant increases of EDV and ESV after being paced for 3 months.This project was supported in part by the Ben B. and Iris M. Margolis foundation. Mr. Werys is supported by a scholarship from the European Union in the framework of European Social Fund through the Warsaw University of Technology Development Program.


Background. General anesthesia is an essential element of experimental medical procedures. Ketamine and isoflurane are agents commonly used to induce and maintain anesthesia in animals. The cardiovascular effects of these anesthetic agents are diverse, and the response of global myocardial function is unknown. Methods. In a series of 15 swine, echocardiography measurements of left ventricular ejection fraction (LVEF) were obtained before the animals received anesthesia (baseline), after an intramuscular injection of ketamine (postketamine) and after inhaled isoflurane (postisoflurane). Results. The mean LVEF of an unanesthetized swine was 47 ± 3%. There was a significant decrease in the mean LVEF after administration of ketamine to 41 + 6.5% (P = 0.003). The addition of inhaled isoflurane did not result in further decrease in mean LVEF . Eight of the swine had an increase in their LVEF with sympathetic stimulation. Conclusions. In our experimental model the administration of ketamine was associated with decreased LV function. The decrease may be largely secondary to a blunting of sympathetic tone. The addition of isoflurane to ketamine did not significantly change LV function. A significant number of animals had returned to preanesthesia LV function with sympathetic stimulation. Anesthesia is frequently required during the medical management of animals for both therapeutic procedures and experimental models. The response of the cardiovascular system to anesthetic agents can be highly variable, based on agent selection, dosing, and the experimental model –3. CommoYoung male domesticated swine, four to eight weeks old and weighing 8 to 12 kg, were used in this study. The research protocol was approved by the Animal Research Committee of Tufts Medical Center and conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care.The anesthesia protocol has been previously published . Swine wEchocardiography was performed at the start of the study prior to ketamine administration, while the animal was being held on the stretcher (baseline). Views included parasternal short and long axis, and apical 2 and 4 chamber. Echocardiography was repeated 5 minutes after ketamine administration, and then again 5 minutes after isoflurane administration. After induction of ventricular fibrillation by ball impact and defibrillation, echocardiocardiography was repeated –15. HearEchocardiograms were reviewed by a single board certified echocardiographer (N.P.) who was blinded to swine specific data and to the stage of the experimental protocol. The global left ventricular ejection fraction (LVEF) was quantitatively assessed as well as the presence or absence of wall motion abnormalities. t tests. Statistical significance was set at a probability value of P < 0.05 with a two sided confidence interval and assuming equal variance. The statistical analyses were run using SPSS Version 17.0. SPSS Inc., IBM Company, 233 S. Wacker Drive, Chicago, Illinois 60606.Results are presented as mean ± standard deviation unless otherwise specified. Data were analyzed using Two-Sample Independent Fifteen swine with a mean weight of 9.9 ± 1.4 kg were used for this analysis. Prior to anesthesia the mean heart rate of the swine was 144 ± 17 bpm and the mean LVEF was 47 ± 3.2%. No wall motion abnormalities were identified at baseline (Tables P = ns). As compared to baseline, there was a significant decrease in the mean LVEF to 41 ± 6.5%, (P = 0.003). A decrease in LVEF was observed in 12 of the 15 (80%) subjects, with 3 subjects showing no change in global left ventricular function . Ten of the 15 (67%) subjects demonstrated an overall further decrease in LVEF with the addition of isoflurane, with the LVEF decreasing by a mean value of 19.6 ± 15.1% from the baseline. There was a slight overall further decrease in mean LVEF, but this value was not significantly lower than after ketamine administration  (Tables After administration of isoflurane, the mean heart rate dropped significantly to 132 ± 22 bpm (After initiation of ventricular fibrillation by baseball strikes to the chest wall and defibrillation, 7 of the 15 animals had a return to preanesthesia LVEF .Ketamine and isoflurane are frequently used in experimental animal models to induce and maintain anesthesia. This is the first study to evaluate the short-term effects of these agents on global myocardial function in a live, whole animal model. Ketamine has significant and varied effects on cardiovascular physiology. The contractility and global LVEF changes documented in this swine model are consistent with a report by Schulte-Sasse et al. that showed short-term elevation of filling pressures with ketamine use in human subjects undergoing coronary artery bypass operations . The dat Recent molecular work might offer further insight for the cardiodepressive effects of ketamine. Specifically, Kawano et al. have demonstrated in an in vitro model that ketamine induces inhibition of sarcolemmal K + ATP sensitive potassium channels . BlockadThere are limited data on the cardiovascular effects of isoflurane in animal models and even fewer reports of the cardiac response in humans. Early reports on human subjects suggest that there are minimal short-term myocardial depressive effects with isoflurane and that the pulmonary capillary wedge pressure does not significantly change , 23. In The molecular basis of isoflurane induced myocardial depression has long been postulated to relate to the regulation of calcium and its relationship to important contractile elements. Isoflurane decreases the amount of calcium present in the sarcoplasmic reticulum . AdditioThe overall short-term myocardial depressive effects of ketamine and the trend towards depressive effects of isoflurane on the swine myocardium have important experimental implications. These short-term changes should be considered when interpreting experimental hemodynamic changes. Additionally, while there have not been systematic evaluations of these agents and their short-term effects on human systolic function, it is reasonable to hypothesize that the human heart undergoes similar short-term changes when exposed to these agents. Lastly, arrhythmic, ischemic, and heart failure disease states in human research studies are all independently associated with decreasing left ventricular ejection fraction –30. It iThere are several limitations to this work. It should be noted that the baseline values in this study were obtained while the animals were excited as they were without anesthesia. As a result, these values may represent a baseline sympathetic-induced increase in ejection fraction . Althoug Ketamine use was associated with a significant short-term decrease in LV function in this experimental swine model. The decrease may be largely due to a blunting of sympathetic tone. The addition of isoflurane to ketamine did not significantly change global LV function. A significant number of animals had returned to preanesthesia LV function with subsequent sympathetic stimulation.


To compare two B1-insensitive T2-preparations to existing techniques regarding cardiac motion and flow robustness.T2-imaging of the heart at 3 Tesla demands T2-preparations not only insensitive to B0 and B1, but also toward cardiac motion and flow in order to avoid flow artifacts and concomitant myocardial contamination and to preserve endocardial border definition. While more refocusing pulses per T2-prep duration improve robustness, they also increase SAR. We chose four BIREF-1 refocusing pulses (one adiabatic fast passage per pulse) to achieve motion-robustness while requiring lower energy than an equal number of pairs of adiabatic fast-passage. We compared two new techniques (NTs) using described scheme to MLEV4 [Healthy volunteers n=18) were scanned  using identical parameters (figure 8 were scBoth NTs resulted in higher image quality and reduced inhomogeneity figure . SignifiTwo new T2-preparation techniques for imaging the heart in vivo have been developed with significantly better performance than existing techniques.


Inflammatory cytokines, cardiomyocyte apoptosis, and altered collagen turnover may contribute to unfavourable ventricular remodeling. This unfavourable ventricular remodelling is well documented in patients after atrial switch operation for complete transposition of the great arteries. We therefore tested if levels of circulating markers of inflammation, apoptosis, collagen synthesis, and extracellular matrix degradation are altered in patients after atrial switch operation for transposition of the great arteries.Circulating tumour necrosis factor (TNF)-α, annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in 27 patients aged 25.2±3.1 years and 20 controls. Ventricular myocardial deformation and left ventricular eccentricity index (EI) were determined by speckle tracking and two-dimensional echocardiography, respectively. Compared with controls, patients had significantly higher circulating AnxA5 (p<0.001) and TNF-α (p = 0.018) levels, but similar PICP, PIIINP, MMP-1 and TIMP-1 levels. For the whole cohort, plasma AnxA5 correlated with serum TNF-α (p = 0.002), systemic ventricular global longitudinal strain (GLS) and systolic and early diastolic strain rate , and subpulmonary ventricular GLS and early diastolic strain rate (both p<0.001). In patients, plasma AnxA5 level correlated positively with subpulmonary ventricular EI (p = 0.027). Multiple linear regression analysis identified systemic ventricular GLS  and serum TNF-α  as significant correlates of plasma AnxA5.Elevated plasma AnxA5 level in patients after atrial switch operation is associated with impaired systemic myocardial deformation, increased subpulmonary ventricular eccentricity, and increased serum TNF-α level. Progressive systemic right ventricular (RV) dysfunction in patients after atrial switch operation for complete transposition of the great arteries (TGA) is well documented The role of inflammatory cytokines in the development of heart failure in congenital heart disease is increasingly unveiled. In adults with congenital heart disease, elevation of serum tumour necrosis factor (TNF)-α level has been associated with severity of heart failure symptoms In the present study, we determined the circulating levels of TNF-α, AnxA5, and biomarkers of collagen synthesis and extracellular matrix degradation including carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients after atrial switch operation for complete TGA. We further explored the relationships of these circulating biomarkers with ventricular myocardial deformation and geometry.All subjects gave written informed consent to participate in this study approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority West Cluster, Hong Kong.Twenty-seven patients with complete TGA who had undergone Mustard or Senning procedure were recruited consecutively from the cardiac clinic. Of these 27 patients, 18 patients had been evaluated previously in a study on diastolic ventricular interaction conducted 2 years ago Transthoracic echocardiography was performed using the Vivid 7 ultrasound system . The echocardiographic data were recorded in digital versatile discs and analyzed offline using EchoPAC software . Measurements of echocardiographic parameters were made over three cardiac cycles and the average was used for statistical analysis.From the apical four-chamber view, two-dimensional speckle tracking echocardiography was performed to determine global longitudinal myocardial deformation of the systemic and subpulmonary ventricles as described previously From the parasternal short-axis view, the subpulmonary left ventricular (LV) geometry of patients was assessed by calculating the diastolic eccentricity index, defined as D2/D1 where D1 is the maximum distance from the surface of the mid-ventricular septum to that of the LV free wall and D2 is the antero-posterior distance measured perpendicular to D1 Venous blood was obtained after echocardiographic assessment and centrifuged immediately after collection. The serum and plasma samples were stored at −80°C until assay. Patient and control samples were run in the same batches to minimize inter-batch variations. Serum TNF-α level was determined by enzyme-linked immunoassay . The standard range is 0.5–32 ng/ml and the sensitivity is 0.11 ng/ml. Plasma Annexin A5 was measured using the commercially available Annexin V-specific ELISA  with a standard range of 0.5–10.7 µg/l and a sensitivity of 0.1 µg/l. The enzymatic activities of serum MMP1 and TIMP1 were measured using the Biotrak ELISA system . For MMP1 assay, the standard range is 6.25–100 ng/ml with a sensitivity of 1.7 ng/ml, while for TIMP1, the standard range is 3.13–50 ng/ml with a sensitivity of 1.25 ng/ml. Serum PICP was measured with immunoassay  with a standard range of 10–640 µg/l and a sensitivity of 2 µg/l. The plasma PIIINP was measured using radioimmunoassay  with a standard range of 1–50 µg/l and a sensitivity of 0.3 µg/l. All measurements were performed in duplicate and the mean was used for further analysis.All data are presented as mean±standard deviation. The demographic variables, echocardiographic parameters, and circulating biomarkers of patients and controls were compared using unpaired Student’s t test. Systemic RV strain indices in patients were compared with systemic LV indices in controls, while subpulmonary LV indices in patients were compared with subpulmonary RV indices in controls. Relationships of the circulating biomarkers found to differ significantly between patients and controls with ventricular strain indices and geometry were assessed using Pearson correlation analysis. Multiple linear regression analysis was further used to identify independent determinants of circulating biomarkers found to be significantly elevated in patients and related to indices of ventricular myocardial deformation. Statistical analyses were performed with SPSS, version 16.0 . A p value less than 0.05 was considered statistically significant while Bonferroni adjustment was made for multiple correlational analyses.2 vs 21.8±3.3 kg/m2, p = 0.96) and body surface area  were similar between patients and controls. By echocardiographic assessment, patients had significantly reduced systemic ventricular GLS and global systolic and diastolic strain rates  compared with controls  aged 25.2±3.1 years at 23.7±2.6 years after atrial switch operation were recruited for evaluation of ventricular myocardial deformation and LV eccentricity. The findings were compared with those of 20 control subjects  aged 25.5±3.8 years (p = 0.75). The body mass index (21.8±3.2 kg/mcontrols . For thePatients had significantly higher plasma AnxA5 (p<0.001) and serum TNF-α (p = 0.018) levels than controls . On the Within the patient group, there were no significant differences in the levels of these biomarkers between patients with and those without additional VSD repair. However, patients on cardiac medications had significantly higher plasma AnxA5 level  and lower subpulmonary ventricular GLS  and tended to have lower systemic RV GLS  compared with those not on medical treatments.For the whole cohort, plasma AnxA5 level correlated negatively with systemic ventricular GLS (p<0.001), SRs (p<0.001), and SRe (p<0.001), and subpulmonary ventricular GLS (p<0.001) and SRe (p<0.001) . Among pSerum TNF-α level correlated positively with plasma AnxA5 level for the whole cohort  . HoweverMultiple stepwise linear regression of the entire cohort was performed to identify significant correlates of plasma AnxA5 level. The independent covariates entered into the model were age, sex, body mass index, systemic and subpulmonary ventricular GLS, SRs, SRe, and SRa, and serum TNF-α level. The significant independent correlates were systemic ventricular GLS  and serum TNF-α level . When only the patient cohort was analyzed with addition of duration after operation, subpulmonary LV eccentricity and the need for cardiac medications to the same list of covariates, the significant determinants of plasma AnxA5 identified were LV eccentricity index  and use of cardiac medications .In the present study, we have demonstrated 1) significant elevation of plasma AnxA5 level in Senning and Mustard patients compared with health subjects, 2) a positive correlation between plasma AnxA5 level and serum TNF-α concentration, and 3) systemic ventricular strain, subpulmonary LV eccentricity, and the use of cardiac medications to be significant determinants of plasma AnxA5 level.Elevation of serum TNF-α in our patients is consistent with findings of previous studies To our knowledge, this is first study to determine plasma AnxA5 level and its relationship with ventricular function and geometry in patients with a systemic right ventricle after atrial switch operation for complete TGA. Clinical studies on the levels and implications of plasma AnxA5 in cardiac patients are limited. Increased plasma AnxA5 has been reported in patients with myocardial infarction 99mTc-annexin uptake and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling The mechanism underlying increased circulating AnxA5 in our patients remains speculative. Stretch-induced up-regulation of AnxA5 has been shown in non-cardiac cells Apart from the quantity of functioning contractile units, integrity of the architectural scaffold of the myocardium is of paramount importance for normal cardiac performance. Increased levels of PICP and PIIINP are found in conditions associated with increased systemic left ventricular afterload and dilated cardiomyopathy Several limitations of this study warrant comments. Firstly, the origin of the various circulating biomarkers assayed in our patients remains to be identified. Secondly, potential confounding influences of cardiac medications on the levels of circulating biomarkers can not completely be excluded. Nonetheless, only 4 of the 27 patients were on cardiac medications at the time of study and we have further performed subgroup analysis based on the use of cardiac medications. Finally, it would have been ideal to determine the relationship between haemodynamic disturbances as tricuspid regurgitation and subpulmonary stenosis and levels of circulating biomarkers in a larger patient cohort.In conclusion, this study provides the first evidence of elevated plasma AnxA5 level in patients after atrial switch operation, which is associated with impaired systemic myocardial deformation and increased serum TNF-α level. The pathophysiologcal significance of an increase in circulating AnxA5 in this adult congenital heart population, however, requires further clarification. Serial longitudinal measurement of plasma AnxA5 level with simultaneous evaluation of clinical status and ventricular function of our patients may shed more light on the potential role of this circulating marker in the monitoring of systemic RV function and prognostication.


Repolarization Gradients in Brugada Syndrome.Introduction: Brugada syndrome (BrS) is associated with loss of Na+ channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/− BrS model, and investigated the effect of flecainide and quinidine upon these.Methods and Results: Langendorff-perfused wild-type and Scn5a+/− hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 μM) or quinidine (5 μM) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/− hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild-type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro- and antiarrhythmic effects. In contrast, Scna5+/− hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis.Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity.  The arrhythmogenicity in BrS is thought to be a result of electrophysiological alterations localized to the right ventricle, reflected in ST elevation in the right precordial leads, right bundle branch block and changes specific to right ventricle (RV) epicardial action potential (AP) waveforms.1 Previous studies have implicated either slowed RV AP conduction3 or alterations in AP repolarization4 in the arrhythmogenesis associated with BrS. Thus, on one hand, reduced Na+ currents in BrS would be expected to compromise AP conduction. On the other, their reduction in relationship to Ito currents in BrS would shorten the RV epicardial APD and consequently permit reentrant waves.5Brugada syndrome (BrS) is associated with a loss of Na+ channel opening by pinacidil, Na+ channel block by flecainide, Ca2+ channel block by verapamil, increased [Ca2+]o, metabolic inhibition or simulated ischemia. Such studies have implicated repolarization gradients caused by regional heterogeneities in electrical activity. However, there is uncertainty as to whether such pharmacological systems provide accurate or complete replication of the physiological changes underlying BrS. Furthermore, the pharmacological manipulations themselves inherently lack a specificity of action. Experimental systems using genetic modifications to replicate BrS may provide a more specific model to clarify physiological abnormalities associated with the disease condition.Experimental models for BrS have involved a number of pharmacological manipulations in canine systems. These have involved use of agents producing KScn5a gene, which encodes the cardiac Nav1.5 α-subunit, has been extensively studied in connection with BrS. Our previous studies using a heterozygotic Scn5a+/− mouse have recapitulated features of the human clinical condition in demonstrating an enhanced arrhythmogenesis that is exacerbated by flecainide and relieved by quinidine. This model has previously shown a 50% reduction in the transmembrane Na+ current and evidence for slowed ventricular and atrioventricular conduction.6 As yet, no evidence has been found for accentuated repolarization gradients in this model although to date no study of the RV has been made.7Thus far, only the 8 and quinidine, which has shown protective actions in symptomatic BrS.9 We correlate alterations in RV gradients in the BrS model that are specifically exacerbated by flecainide, with the observed arrhythmogenic properties and with clinical findings implicating the RV in the arrhythmogenic mechanism. This may contribute to future work investigating possible pharmacological treatments for a disease for which the current mainstay of treatment is implantable cardioverter defibrillator (ICD) implantation.5In the present experiments, we seek for the first time in a genetic whole-heart BrS model to discriminate the contributions of alterations in conduction and repolarization gradients in the arrhythmogenesis, and to localize the pathophysiological mechanism in the RV. We were particularly interested in the effects upon conduction velocity and repolarization gradients of 2 clinically used drugs: flecainide, which is known to unmask ventricular arrhythmogenesis in otherwise asymptomatic BrS patients,Scn5a+/− and wild-type (WT) inbred 129/sv mice initially supplied by Harlan (UK). Experiments used a Langendorff-perfused preparation adapted for the murine heart, as described previously.10 Following the start of perfusion, viable hearts suitable for subsequent experimentation regained a pink coloration and spontaneous rhythmic contraction with warming. Where used, 10 μM flecainide and 5 μM quinidine  dissolved in buffer solution were perfused for 15 minutes prior to and throughout data acquisition. Concentrations were within the same range as known clinical therapeutic levels .11 All procedures conformed to the UK Animals (Scientific Procedures) Act 1986.Mice aged 4–8 months were obtained from breeding pairs of heterozygote 12 Epicardial MAPs were recorded from the basal surface of the ventricular epicardium, both on the left and on the right using a miniaturized MAP electrode tip . Endocardial MAPs used electrodes constructed from galvanically chlorided, Teflon-coated 0.25 mm diameter silver wire introduced into the ventricular cavity through a small access window created in the ventricular wall. Pilot experiments showed that both sets of electrodes provided equivalent MAP traces. MAP signals were amplified and band-pass filtered between 0.1 Hz and 300 Hz , then digitized using a 1401plus interface . Paired platinum stimulating electrodes paced the heart high on the interventricular septum.Monophasic action potentials (MAPs) were recorded using an established contact-electrode technique detailed previously.The stimulating electrode and the epicardial LV and RV recording electrodes were clamped at a constant position through all experiments. This was at a distance of approximately 10 mm between stimulating and each recording electrode, although it was slightly larger for the LV than for the RV. This distance allowed the hearts to be placed into the rig, with the stimulating electrode coming into contact with the septum and the recording electrodes coming into contact with the left and right ventricles. While the direct absolute distance between electrodes would not necessarily reflect the path through which the electrical signal would be conducted in the spherical whole heart, the fact that the distance was maintained between experiments allowed consistent measurements of activation latencies. As the clamp was secure throughout experiments, this distance was constant to ∼0.5 mm, i.e., 5% of the distance between stimulating and recording electrodes.For measurement of APDs, hearts were paced at 8 Hz for 5 minutes and recordings were made at LV and RV, epicardial and endocardial sites. For activation latencies, only epicardial sites were used, as the point of endocardial recording could not be accurately determined. For calculations of arrhythmia incidence, as well as regular 8 Hz pacing, the hearts also underwent an S1S2 protocol, imposing S2 extrastimuli following pacing S1 stimulus trains at S1–S2 intervals, reduced by 1 ms between successive drive trains until the preparation became refractory, and a dynamic pacing protocol progressively increasing pacing frequency every 100 beats. Thus for each heart, 12 recordings in total were made, with 3 protocols and 4 cardiac regions employed. MAP recordings were made both before and during treatment with either flecainide (10 μM) or quinidine (5 μM).x measurements at x = 90% (APD90), 70% (APD70) and 50% (APD50) repolarization. The effect of heterogeneous repolarization on the difference between different cardiac regions was expressed empirically as the difference (ΔAPDx) between neighboring APD values: LV transmural = LV endocardial APD—LV epicardial APD, RV transmural = RV endocardial APD—RV epicardial APD, epicardial transventricular = LV epicardial APD—RV epicardial APD, endocardial transventricular = LV endocardial APD—RV endocardial APD.MAP waveforms were analyzed using Spike2 software (Cambridge Electronic Design). The point of maximum positive deflection was considered the point of 0% repolarization; that of full return to baseline of 100% repolarization. The intervening waveform was described in terms of APDScn5a+/− hearts, and before and after drug. However, as the distance from stimulating electrode on the septum was slightly greater to the LV recording electrode than the RV recording electrode, no direct comparison could be made between LV and RV. For the calculation of arrhythmic incidence, each run was labeled as either nonarrhythmic or showing one of 3 possible arrhythmias: VT (exceeding 1 second in duration), nonsustained VT , or having one or more ventricular ectopic (VE).Activation latencies for MAPs recorded from the RV and LV epicardium were measured from the stimulus time to peak amplitude of the MAP to give an indication of conduction velocities. With the positions of the stimulating and recording electrodes constant between experiments, comparisons could be made between WT and Scn5a+/− mice were used in our experiments, as this was a number sufficient to enable categorical statistical analysis for incidence of arrhythmogenesis. Although we also attempted quantitative measurements in all 16, we only included measurements from hearts whose MAPs strictly attained the accepted criteria of rapid upstroke phases, consistent amplitudes, smooth contoured repolarization phases and stable baselines13 in all 4 cardiac regions. We consequently used 12 hearts of each genotype for the calculation of activation latencies and repolarization gradients. In all cases, half of each group was exposed to flecainide and 6 to quinidine.Sixteen WT and 16 t-tests; these were paired where results could be compared from the same heart. Previously, ANOVA with post-hoc Tukey's honestly significant different tests have been used to analyze multiple paired data sets; however, this assumes that all data sets are compared with each other and thus increases the likelihood of Type II errors. We accordingly adopted a procedure using a modified Bonferroni correction factor14 using the following procedure: t-tests were grouped into independent data sets and the significance values rank-ordered from smallest to largest. The significance of the test with P-value at alpha/(number of tests) was evaluated and, if statistically significant, the test result from the test with the next smallest significance value was selected and evaluated at alpha/(number of tests—1), and so on. Alpha was set at 0.05.All results were expressed as mean ± S.E.M. values. The significance of differences in arrhythmic incidences used Fisher exact and Chi-squared tests. Differences in activation latencies, APDs and ΔAPDs between different regions were analyzed using Student's Scn5a+/− hearts could either be resistant to arrhythmia or could show VEs, nsVT, or polymorphic VT during recording. Scn5a+/− hearts during regular 8 Hz pacing. Similar traces could be obtained from WT, and from other cardiac regions in both Scn5a+/− and WT.WT and Scn5a+/− hearts showed markedly greater arrhythmic tendencies. In both cases, Fisher exact tests excluded significant differences in arrhythmia incidence between cardiac region or stimulus protocol . These results were therefore combined for Chi-squared testing sorted by genotype and drug condition  in both the LV and RV of both WT and Scn5a+/− hearts.In comparison with WT hearts, nduction . HoweverScn5a+/− heart, overlaid to demonstrate the contrasts in LV and RV transmural  the resulting gradients between them expressed as ΔAPD70s across neighboring regions. Thus,We then undertook a systematic comparison of epicardial and endocardial MAP waveforms in both RV and LV. ansmural  and epicansmural . Figure Scn5a+/− hearts showed significant repolarization gradients varying between different cardiac regions. These gradients were particularly strong at earlier  phases of the AP recovery and arose from the following findings of the individual MAP durations. Endocardial MAP durations were very similar in the LV and RV. In contrast, epicardial MAP durations in the RV were shorter than those in the LV of both WT and Scn5a+/− hearts. Finally, both the RV and LV endocardial MAPs were longer than their corresponding epicardial MAPs, giving statistically significant differences in the RV in both WT and Scn5a+/− hearts. These differences resulted in RV transmural gradients that were significantly greater than the corresponding LV gradients, particularly in the Scn5a+/− hearts.Both untreated WT and Scn5a+/− hearts showed generally shorter APDs than WT. Although this was true of all ventricular regions, this only reached statistical significance in the RV epicardium. This resulted in significantly greater RV transmural gradients, as reflected in the ΔAPD50, ΔAPD70, and ΔAPD90 values in Scn5a+/− hearts compared with WT.Scn5a+/− through accentuated RV transmural repolarization gradients, brought about by shortened RV epicardial APDs. This hypothesis could be tested by assessing the extent to which the actions of flecainide and quinidine upon these gradients in Scn5a+/− compared with WT paralleled their respective pro- and antiarrhythmic actions in Scn5a+/−.The findings above implicate the RV in the arrhythmogenicity shown by Scn5a+/− hearts into age and sex matched groups for studies before and following treatment with 10 μM flecainide or 5 μM quinidine (n = 6 hearts in each group). Scn5a+/− hearts as in 70s from the RV epicardium, and (F) the resultant RV transmural ΔAPD70s for WT and Scn5a+/− hearts before and after drug treatment.The resulting experiments split the WT and These demonstrated the following:90.In WT hearts, flecainide shortened the APD values in all 4 ventricular regions investigated, but doing so significantly only for RV epicardium. This resulted in increases in the RV transmural gradients, but which only reached significance for the APD90.In WT hearts, quinidine increased the APD values in all the ventricular regions studied, but did so most noticeably in the RV epicardium, reaching significance here for all 3 repolarizations. The RV transmural gradient was reduced, but again only reaching significance for the APDScn5a+/− hearts, flecainide shortened the APD values in all the ventricular regions studied. Again, this effect was most noticeable in the RV epicardium. This resulted in marked increases in the RV transmural gradient whether measured as ΔAPD50, ΔAPD70, or ΔAPD90. There were no significant alterations in either the transventricular or the LV transmural gradient.In Scn5a+/− hearts, again reaching significance specifically in the RV epicardium. These changes markedly decreased the RV transmural gradients to levels similar to that seen in WT before pharmacological treatment, but did not significantly reduce either the transventricular or LV transmural gradients.In contrast, quinidine lengthened the APDs in all ventricular regions in Scn5a+/− as WT hearts, particularly involving the RV epicardium, with quinidine reducing, and flecainide increasing, the RV transmural gradients. However, the latter maneuvers acted upon a situation of already accentuated right transmural gradients in the Scn5a+/−, thereby giving very strongly positive RV transmural gradients.The pharmacological maneuvers thus exerted similar patterns of effects upon + channel mutation. This prompted the recent development and use of a Scn5a+/− murine genetic model in studies of the BrS condition. Having first confirmed arrhythmogenicity in the Scn5a+/− hearts, we systematically investigated arrhythmic incidence in all 4 cardiac regions with 3 different stimulation protocols for the first time. We demonstrated that this model reproduces the clinical BrS condition by displaying ventricular arrhythmias that were exacerbated by flecainide, in line with its clinical effects in unmasking ventricular arrhythmogenesis in otherwise asymptomatic BrS patients,8 and reduced by quinidine, in line with its protective action on symptomatic BrS.9 Equal arrhythmia incidence in all 4 cardiac regions is consistent with arrhythmic activity arising in any one cardiac region ultimately spreading throughout both ventricles, therefore involving the entire heart. That stimulation protocol did not significantly affect arrhythmogenic incidence is consistent with clinical observations that the inducibility of VT during PES fails to predict sudden cardiac death in BrS patients.15The BrS has been associated with a heterogeneous group of genotypes; nevertheless, ∼15% of BrS patients do show a loss-of-function NaScn5a+/− hearts. Such findings complement previous reports of Scn5a+/− myocytes having Na+ current amplitudes reduced to ∼50% of the levels shown by WT, as well as slowed AP conduction.6 Our study supports earlier work measuring regional APDs in canine16 and rat17 WT systems, as well as molecular and cellular studies of regional ion channel location.21 The present results also extend findings of altered repolarization gradients in canine wedge preparations that mimic BrS by pharmacological rather than genetic means.22 However, our study is the first using a genetic model for BrS and in which all 4 cardiac regions have been systematically compared.The differences in arrhythmic properties could be associated with both delayed epicardial activation latencies and increased right transventricular repolarization gradients in 23 or it is secondary to conduction slowing.24 The localization of the enhanced repolarization gradients to the RV may suggest that the physiological mechanism underlying ST elevation is also more closely related to a repolarization disorder than a delay in depolarization.Comparison of such altered conduction and repolarization properties through the epicardia and endocardia of the right and left ventricles demonstrated that while both slowed conduction and accentuated repolarization gradients could potentially contribute to the arrhythmogenic mechanism in BrS, it was only the repolarization abnormalities that could be localized to the RV epicardium. Thus, while conduction slowing may provide a background arrhythmic substrate, the RV origin of the arrhythmias in clinical BrS suggests that the heightened repolarization gradients in this region may be the specific trigger. These findings also shed light on the pathophysiology of ST elevation seen in BrS, for which 2 mechanisms have been proposed: either it is due to the difference in AP morphology between the RV epicardium and endocardium,2 that is exacerbated with class 1C drug challenge.3 The latter result supports findings in canine models, where high flecainide concentrations result in loss of the AP dome and marked AP abbreviation,25 and clinical studies demonstrating that pilsicainide administration in BrS patients triggers T wave alternans, which is known to reflect enhanced spatial and temporal dispersion of repolarization.26 However, whereas the action of flecainide on activation latencies occurred in both the RV and the LV, its action on transmural repolarization gradients was again significant specifically for the RV.The increase in both latencies and transmural gradients produced by flecainide correlates with its proarrhythmic effects in both the model and clinical situations. The former finding parallels the clinical findings implicating slowed conduction in the RV outflow tract in Brugada patients+ channels, but is in contrast to its effect in decreasing arrhythmic incidence in murine Scn5a+/− and human BrS hearts. On the other hand, its action in reducing transmural repolarization gradients correlated with its antiarrhythmic effects. Quinidine has correspondingly been shown to reverse the associated electrocardiographic abnormalities and prevent phase 2 reentry and polymorphic VT in experimental canine BrS models,22 and normalize the ST segment in clinical circumstances.28The increase in conduction delay produced by quinidine was not unexpected given its effect in blocking Na29 This means that the spike and dome morphology present in larger mammals is not present in our mouse model. However, despite these difficulties, we were able to demonstrate a clear propensity to arrhythmia in our BrS mouse model and correlate this with enhanced RV transmural gradients.The main limitations of the study are associated with the differences between mouse and human physiology. The small size of the mouse heart means that strong electrotonic forces may act to minimize the effect of any spatial heterogeneities that are created and reduce their potential to create reentrant substrate. The AP morphology differs between humans and mice, as mice use less L-type Ca channel current, which means that the mouse AP does not have a plateau phase and has a shorter APD.Scn5a+/− hearts with both increased activation latency and decreased RV epicardial APD and increased RV ΔAPDs. However, while conduction delay was not localized specifically to the RV and was increased by both flecainide and quinidine, the respective pro- and antiarrhythmic effects of flecainide and quinidine could be directly correlated with their actions in increasing and decreasing RV ΔAPDs. Thus, these findings, while not excluding a contribution of conduction delay, support most closely an arrhythmogenic trigger based on reentry from abnormal repolarization gradients between RV epicardial and endocardial sites.In summary, this study has for the first time in a genetically modified BrS model assessed activation latency, APDs and derived AP repolarization gradients from 4 regions of the heart under a range of stimulation protocols and a range of pharmacological conditions. The experiments correlate the increased arrhythmogenicity in


Performance of the left ventricle during exercise stress in thalassaemia patients is uncertain. We aimed to explore the phenomenon of dynamic dyssynchrony and assess contractile reserve in patients with beta-thalassaemia major and determine their relationships with myocardial iron load.exercise-baseline correlated with exercise-baseline differences in LV ejection fraction (p<0.001) and stroke volume (p = 0.006). Compared with controls, patients had significantly less exercise-induced increase in LV ejection fraction, cardiac index, and IVA  and had impaired contractile reserve as reflected by the gentler IVA-heart rate slope (p = 0.018). Cardiac T2* in patients correlated with baseline LV SDI  and IVA-heart rate slope .Thirty-two thalassaemia patients , aged 26.8±6.9 years, without heart failure and 17 healthy controls were studied. Their left ventricular (LV) volumes, ejection fraction, systolic dyssynchrony index (SDI), and myocardial acceleration during isovolumic LV contraction (IVA) were determined at rest and during submaximal bicycle exercise testing using 3-dimensional and tissue Doppler echocardiography. Myocardial iron load as assessed by T2* cardiac magnetic resonance in patients were further related to indices of LV dyssynchrony and contractile reserve. At rest, patients had significantly greater LV SDI (p<0.001) but similar IVA (p = 0.22) compared with controls. With exercise stress, the prevalence of mechanical dyssynchrony  increased from baseline 25% to 84% in patients. Δ SDIResting LV dyssynchrony is associated with myocardial iron load. Exercise stress further unveils LV dynamic dyssynchrony and impaired contractile reserve in patients with beta-thalassaemia major. Iron-induced cardiomyopathy is well documented in patients with beta-thalassaemia major In patients with beta-thalassaemia major, substrate for development of LV dynamic dyssynchrony potentially exists. In dilated cardiomyopathy, development of ventricular dyssynchrony has been attributed to progressive myocardial fibrosis Assessment of contractile reserve using ejection-phase indices is difficult in the setting of thalassaemia, as these indices are strongly load-dependent. Recently, non-invasive assessment of changes in myocardial acceleration during isovolumic LV contraction (IVA), a relative load-independent index of contractility, with increased heart rate during exercise stress has been shown to be useful in assessing contractile reserve based on the force-frequency relationship In the present study, we explored the phenomenon of dynamic dyssynchrony and assessed contractile reserve, using respectively exercise three-dimensional and tissue Doppler echocardiography, in patients with beta-thalassaemia major. We further determined in these patients the relationships between myocardial iron load and baseline LV mechanical dyssynchrony and exercise-induced changes in LV dyysynchrony and IVA.The Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster approved the study and all subjects gave written, informed consent.Patients with beta-thalassaemia major and without overt congestive heart failure were recruited from the haematology clinic. Healthy non-paid subjects, including siblings and staff volunteers, were recruited as controls. The body weight and height were measured and body surface area was calculated accordingly. The Institutional Ethics Committee approved the study and all subjects gave informed consent.All subjects had echocardiographic evaluation during rest condition and supine bicycle exercise. In addition, patients underwent T2* cardiac magnetic resonance imaging for determination of myocardial iron load. In patients, cardiovascular assessment was performed within 2 weeks of blood transfusion so as to minimize potential confounding influence of anaemia. Their surface electrocardiograms were assessed for QRS prolongation and evidence of cardiac arrhythmias.Pulsed tissue Doppler imaging of the apical 4-chamber view was performed with the sample volume positioned at the junction of the LV free wall and mitral annulus. The following parameters were determined: systolic (s) and early (e) and late (a) diastolic annular velocities, e/a ratio, and IVA Real-time 3D echocardiographic imaging of the left ventricle was performed from the apical view using a matrix array transducer . Full-volume acquisition with capturing of 4 adjacent sub-volumes over 4 consecutive cardiac cycles was performed during breathhold.Offline analysis was performed using commercial 4D analysis software . Three slices  of the left ventricle at end-systole and end-diastole were defined and the endocardial border in each of the slice was traced semi-automatically. A LV cast was created for derivation of LV end-diastolic and end-systolic volumes, based on which the ejection fraction, stroke volume and cardiac output were determined.The LV cast was then divided pyramidal subvolumes based around a non-fixed central point, and the time-volume data corresponding to each of the 16 standard myocardial segments as defined by the American Society of Echocardiography were obtained. Left mechanical mechanical dyssynchrony was quantified by the systolic dyssynchrony index (SDI), calculated as the SD of time to reach minimum regional volume for each of the segments as a percentage of the cardiac cycle duration Exercise testing was performed with a supine bicycle according to the McMaster cycle ergometer protocol. The initial workload was 25 W with a 25 W increase in resistance at 2-minute intervals. Three-dimensional echocardiographic data for assessment of ventricular dyssynchrony and LV IVA were collected at baseline and when the heart rate reaches 70% of the age-predicted peak heart rate. Given the well documented impaired exercise capacity of thalassaemia patients with significant iron overload The T2* scan was performed by a 1.5T Siemens Sonata scanner as described previously exercise-baseline/Δheart rateexercise-baseline. Analysis of variance with two factors was used to determine the effect of group (patients vs controls) or the effect of exercise (baseline vs exercise) or interaction of the two. Comparison of demographic variables and delta changes from baseline to exercise of echocardiographic variables between patients and controls were performed using unpaired Student’s t test. Left ventricular mechanical dyssynchrony was defined as LV SDI exceeding mean+2SD as derived from baseline control data at rest. Multiple linear regression analysis was used to determine significant correlates of IVA-heart rate slope. The intra- and interobserver variabilities of baseline and exercise LV ejection fraction and SDI were reported as coefficients of variation, calculated by dividing the SD of differences between measurements by the mean and expressed as a percentage. One of the coauthors (WY) performed repeated measurements in the same offline analysis session to assess intraobserver reproducibility, while two readers (WY and SJW) performed blinded repeated measurements to determine interobserver variability. Within group analyses using Pearson correlation was performed to assess for associations between the cardiac T2* findings and baseline LV dyssynchrony, ejection fraction, changes in dyssynchrony index during exercise stress, and contractile reserve. A p value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 11.5 .All data are presented as mean±SD. The LV volumes, stroke volume and cardiac output were indexed by body surface area. The IVA-heart rate slope was calculated by the formula: ΔIVAThirty-two patients  aged 26.8±6.9 years were studied. The types of chelation therapy at the time of study included deferiprone with deferoxamine in 20 patients, deferoxamine in 5 patients, deferasirox in 5 patients, and deferiprone in 2 patients. A total of 17 healthy subjects , aged 25.3±4.8 years (p = 0.43), were recruited as controls. Compared with controls, patients were lighter (p = 0.045) and having a smaller body surface area (p = 0.013) . All of At baseline, patients had lower mitral annular s velocity and LV IVA compared with controls. On the other hand, the two groups had similar mitral annular e and a velocities, and e/a ratio. The LV ejection fraction was lower and indexed LV end-systolic volume was greater in patients than controls, while the indexed LV end-diastolic volume and cardiac index were similar between the two groups.The supine bicycle exercise testing parameters are summarized in For reproducibility of LV SDI measurements, the coefficients of variation for intra- and inter-observer measurements were respectively 7.7% and 9.7% at rest, and 11.7% and 11.0% when target heart rate was reached during exercise.The resting LV SDI was significantly greater in patients than controls  . Based oIn patients, the cardiac T2* finding correlated negatively with baseline LV SDI  and positively with LV ejection fraction . Using 20 ms as a cutoff for significant myocardial iron overload During exercise, the LV SDI remained significantly greater in patients than controls . Analysis of variance similarly revealed significant differences between groups  and between exercise and baseline  in terms of LV SDI. The prevalence of LV dyssynchrony in patients increased to 84% (27/32) during exercise when the target heart rate was achieved . Figure Dynamic dyssynchrony was quantified by the difference between exercise and baseline SDI (Δ SDI). Compared with controls, patients had significantly greater Δ SDI  . ΔSDI coThe LV IVA, while similar between the two groups at baseline (p = 0.22), was significantly lower in patients during exercise (p = 0.001) . FurtherIndependent correlates of IVA-heart rate slope in patients as identified from multivariate regression analysis were T2*  and body weight  after adjustment for age, gender, body height, and baseline heart rate, IVA, LV ejection fraction, and exercise-baseline differences in LV ejection fraction.The novel findings of this study are that in patients with beta-thalassaemia major 1) resting LV mechanical dyssynchrony occurs with a prevalence of 25%, 2) dynamic dyssynchrony and impaired contractile reserve of the left ventricle are evident at even submaximal exercise stress, and 3) baseline LV SDI and contractile reserve during stress correlate with myocardial iron load. To our knowledge, this is first study to assess dynamic changes in LV mechanical dyssynchrony and cardiac contractile reserve in iron-loaded thalassaemia patients during exercise stress.Dyssynchronous contraction of LV myocardium is recognized as an important factor that may contribute to global LV systolic dysfunction Dynamic dyssynchrony has been demonstrated in hypertensive heart failure patients with normal ejection Whether ventricular dyssynchrony is a marker of heart failure or that it contributes to the pathophysiology of heart failure has been a matter of debate. Nonetheless, our finding of ventricular dyssynchrony even in patients without clinical cardiac failure, the reported relationship between ΔSDI and changes in LV output during exercise in this and previous studies The mechanism of LV dyssynchrony and its exaggeration during exercise stress in thalassaemia patients remains speculative. The possible contribution of progressive patchy fibrosis with evidence from histological examination The significant relationship between cardiac T2* measurement and LV SDI at rest suggests that myocardial iron load probably plays an important role in its pathogenesis. Ferrous iron interacts with ryanodine-sensitive calcium channels responsible for the activation of myocardial contraction and modulation of calcium uptake in the sarcoplasmic reticulum The positive force-frequency relationship, which reflects intrinsic myocardial performance, is related to increased and more efficient calcium cycling as heart rate increases Our findings of resting and dynamic mechanical dyssynchrony and impaired contractile reserve of the left ventricle and their relationships with myocardial iron load in thalassaemia patients have important clinical implications. Intensification of iron chelation therapy may improve not only resting LV systolic function The cross-sectional design of the present study has its inherent limitations. While the presence of LV dyssynchrony in adults with heart failure has been demonstrated to have prognostic implications in terms of risk of cardiac events and mortality In conclusion, we have provided novel data that suggest resting and dynamic mechanical dyssynchrony and impaired contractile reserve of the left ventricle in patients with beta-thalassaemia major. These findings may offer new perspectives for the understanding and management of iron-induced cardiomyopathy.


The aim of our study was to assess regional myocardial perfusion and oxygenation in patients with Syndrome X and in normal volunteers, using cardiovascular magnetic resonance (CMR) imaging at 3 Tesla.The pathophysiology of chest pain in patients with Syndrome X remains controversial. Previous studies using nuclear techniques or CMR to assess myocardial perfusion have shown conflicting results. Advances in perfusion imaging with CMR now enable absolute quantification of regional myocardial blood flow. Furthermore, blood oxygenation level-dependent (BOLD) CMR provides the unprecedented capability to assess regional myocardial oxygenation. We hypothesized that the combined assessment of regional perfusion and oxygenation with CMR could clarify whether patients with cardiac Syndrome X show evidence of myocardial ischemia (reduced perfusion and oxygenation) during vasodilator stress compared to normal volunteers.18 patients (15 women) with Syndrome X  and 14 age and sex-matched normal volunteers (11 women) underwent CMR scanning at 3 Tesla. Myocardial function (cine CMR), scar (late gadolinium enhancement), perfusion and oxygenation were assessed. For perfusion, 2-3 short axis slices were acquired (depending on heart rate response to stress) with a saturation recovery fast-gradient echo sequence and 0.04 mmol/kg Gd-DTPA bolus. Absolute myocardial blood flow (MBF) was measured during adenosine stress (140μg/kg/min) and at rest by model independent deconvolution after saturation correction. Rest MBF was corrected for rate-pressure product. For oxygenation, using a T2-prepared blood oxygen level dependent (BOLD) SSFP sequence, signal intensity was measured at stress and rest in the slice matched to the mid-slice of the perfusion test.All subjects successfully completed the study protocol. There were no differences in LV volumes and ejection fraction between patients and normal controls. No subject had evidence of late gadolinium enhancement. Myocardial blood flow at stress, BOLD signal change, and coronary flow reserve measurements showed no significant differences in Syndrome X patients and controls (see table Patients with Syndrome X have no reduction of absolute perfusion or impairment in oxygenation during vasodilatory stress. Our findings are in contrast to other CMR studies and might reflect differences in patient population and CMR methodology (absolute vs relative quantification of perfusion).


Trials have brought diverse results of bone marrow stem cell treatment in necrotic myocardium. This substudy from the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial (ASTAMI) explored global and regional myocardial function after intracoronary injection of autologous mononuclear bone marrow cells (mBMC) in acute anterior wall myocardial infarction treated with percutaneous coronary intervention.Cardiovascular magnetic resonance (CMR) tagging was performed 2-3 weeks and 6 months after revascularization in 15 patients treated with intracoronary stem cell injection (mBMC group) and in 13 controls without sham injection. Global and regional left ventricular (LV) strain and LV twist were correlated to cine CMR and late gadolinium enhancement (LGE).In the control group myocardial function as measured by strain improved for the global LV  and for the infarct zone , and significantly more than in the mBMC group . LV infarct mass decreased , also significantly more pronounced than the mBMC group (inter-group p = 0.034). LV twist was initially low and remained unchanged irrespective of therapy.LGE and strain findings quite similarly demonstrate subtle differences between the mBMC and control groups. Intracoronary injection of autologous mBMC did not strengthen regional or global myocardial function in this substudy.NCT00199823ClinicalTrials.gov:  Different studies have brought diverse results on the effects of cell therapy in acute myocardial infarction. Effect measures have included clinical parameters and measurements of global left ventricular (LV) function obtained through a spectrum of methods-6. Some Methods and techniques used in the ASTAMI trial have been reported in detail previously. BrieflyCine images, tagging sequences and late enhancement images were acquired in the same image session with 1.5 tesla units  with a phased array body coil.Two cine long axis projections of the left ventricle were acquired with either a breath-hold segmented spoiled gradient echo sequence, fast low angle shot (FLASH) or a breath-hold segmented balanced gradient echo sequence, fast imaging with steady-state free precession (trueFISP). Each patient had either paired FLASH or paired trueFISP examinations. Temporal resolution was 50 ms or less and slice thickness was 6 mm.Tagged CMR of the left ventricle was obtained with a FLASH sequence. Three short axis levels were standardized with the basal level just apical to the mitral ring at end-systole, the mid-ventricular level on the mid-point of the left ventricular long axis, and apical level just basal to the level of luminal closure at end-systole. Orthogonal tags in a grid pattern were parallel or perpendicular to the 2-chamber long axis plane with distance between tags of 8 mm. Temporal resolution was less than 50 ms and slice thickness 6 or 8 mm.Late enhancement images were obtained 10 - 20 minutes after intravenous injection of 0.2 mmol/kg gadopentetate dimeglumine  in two long axis projections corresponding to the cine images and multiple short axis projections covering the LV with a breath-hold inversion recovery turbo gradient echo sequence. The inversion time was chosen to null the signal of the normal myocardium. Slice thickness was 7 or 8 mm and increment between slices was 10 mm.All CMR analyses were performed blinded to treatment allocation. End diastolic volumes (EDV), end systolic volumes (ESV) and EF were calculated according to the biplane area-length method from the two long axis cine projections.Tagging recordings were analyzed with Harmonic Phase Imaging . For each slice, 24 mid-wall points were semi-automatically tracked, and circumferential Lagrangian end systolic strain was calculated from deformation of the line between points. Each of the 24 strain measurements were manually assigned to the 16 segment model, and meaSegments were excluded for further analysis if more than half of the segment's strain curves had been excluded due to noise. The LV regions were excluded for further analysis if more than half of the segments in the region had been excluded. Global mean strain values were excluded if more than 50% of the segments had been excluded or if either the basal, mid-ventricular or apical slices suffered from missing segmental data.LV rotation data were obtained from the mid-wall tracking also made for strain analysis in the basal and apical slices, values given in degrees. LV twist was calculated as basal rotation subtracted from apical rotation. Strain and twist inter- and intra-observer reproducibility was assessed through repeated analyses of 10 randomly chosen tagging examinations.Late enhancement short axis slices were manually assigned to basal, mid or apical left ventricular slices and divided into sectors to fit the 16 segment model. MyocardLGE and strain data were analyzed globally and in corresponding LV regions, based on baseline LGE findings. All infarct segments in each patient were summarized, denoted infarct zone. All segments without late enhancement were denoted remote segments. Segments with more than 75% infarct were studied selectively, denoted transmural infarct zone, corresponding to the transmurally infarcted segments studied by Herbots et al..Categorical variables were analyzed with the chi-square test. Continuous data are presented as mean ± standard deviation, and in the gross material all variables for baseline and end-point analyses approximated a normal distribution. For comparisons between groups at baseline two-sample t-tests were performed. Intra-group changes were evaluated by paired sample t-tests. Development between 2-3 weeks and 6 months was assessed by analysis of covariance, with the baseline values used as a covariate. Corresponding analyses were performed on patients with lower than median EF at baseline CMR. Owing to the relatively low number of patients inter-group comparisons were performed with the non-parametric Mann-Whitney test and intra-group change was evaluated with the Wilcoxon signed ranks test. For tagging reproducibility two-way mixed absolute agreement intraclass correlation analyses of global and regional strain and twist were performed. The intraclass correlation coefficients (ICC) are presented with 95% confidence interval. SPSS software version 16.0 was used. Tests were two-sided, and p-values < 0.05 were considered statistically significant.Among all patients, the mean age was 58.6 ± 9.1 years, mean time from the onset of symptoms to PCI was 234 ± 104 minutes, and the mean value for maximum creatine kinase MB was 361 ± 136 μg per liter. The characteristics of the patients at admission did not differ significantly between the two groups  and ESV decreased significantly  in the control group but did not change in the mBMC group.Average segmental LGE at baseline is illustrated in Figure Average segmental strain at baseline is illustrated in Figure LV function as measured by global strain improved significantly from baseline to 6 months in the control group , but remained unchanged in the mBMC group. In the control group, regional myocardial function improved significantly in the infarct zone , but not in the transmural infarct zone or the remote segments. Regional myocardial function remained unchanged in the mBMC patients. In the group of patients with low baseline EF, strain improvement was significantly more pronounced for the controls in the transmural infarct zone only. LV twist was analyzed in all 28 patients. Twist was low at baseline for both groups, and did not change significantly over time in either of the groups. The ICC of agreement for inter-observer judgments was 0.92 (0.74-0.98) and for intra-observer observations 0.96 (0.85-0.99).The changes of LV strain in the control group correlated significantly with LV infarction mass at baseline and change of LV infarction mass Table .The ASTAMI study, which included 100 patients, was originally designed with a power of 80% to reveal a potential difference of 5% points of LV EF development between the mBMC and the control groups as measured by single-photon-emission computed tomography. No difference was found for global functional development or for clinical parameters,21. For Care must be taken drawing conclusions from the results regarding development of myocardial function and LGE in this study. Recently, Beitnes et al. published results from the long-term follow-up of the ASTAMI trial including global and regional LAD strain analyses performed with longitudinal two-dimensional speckle-tracking echocardiography 2D STE). They reD STE. ThIn the main ASTAMI study, 72% of the patients who received intracoronary cell injections reported mild chest pain during the procedure and 77% had transient ischemic ST deviation during balloon inflation. No patient had reinfarction related to the procedure. Thus, tRegional wall function has been investigated by different means in other stem cell trials. In the Repair-AMI trial regional function improved more in infarcted areas in the stem cell group judged by the centerline chord method at 4 months. In a reEnd systolic LV twist is the difference in the systolic clockwise rotational movement of the basal region from the counter-clockwise rotational movement of the apical region as seen from the apex. The rotation is part of the complex wringing movement of the left ventricle during systole,28. BaseAccording to the standardized scheme for myocardial territory assignment the LAD artery supplies the anterior wall and the anterior part of the septum, as well as the apical septum and the apical cap. Ortiz-PThe time point for the baseline CMR at least two weeks after the acute event was chosen to reduce overestimation of infarct size owing to tissue edema, and T2-weighted sequences for evaluation of edema were therefore not part of our protocol. Obviously, more information on LV volumes and function could have been available with an additional CMR examination before or immediately after intracoronary cell injection. Thus, we may have missed early and short term changes after the injection, and thereby possible differences between the groups, either related to stem cell effect, or even to the intracoronary balloon inflation procedure itself. This fact also is relevant for the direct comparison between echo and CMR results. However, the time point for baseline CMR examination was suitable for the investigation of myocardial remodeling after the acute phase. Serial CMR studies underscore the advantages of examining LGE after the first 7 days of resorption of necrotic myocardium and hemorrhage, reduction of myocardial edema and possibly rescue of myocardium at risk. A better correlation was found between later functional parameters and LGE after one week compared with LGE immediately after the infarction and reperfusion-37.Short duration of follow-up and a relatively small number of patients, even reduced by exclusions from tagging noise; make the present study insufficient in the assessment of post mBMC treatment effects. LV EF was examined with the area-length method, possibly adding variability compared with multiple short-axis cines. Differences in development may have been masked. The selection of patients did not completely concur with the main ASTAMI study, with a non-significant, numerically slightly higher initial infarct mass in the control group than the mBMC group.The results from the present study do not support the hypothesis that intracoronary mBMC injection after reperfused anterior wall infarction reduces infarct size or improves myocardial function. Findings from regional LGE and strain analyses quite similarly demonstrate subtle differences between the mBMC and control groups with a slightly more favorable development in the controls. The potential role for LV twist as assessed by CMR tagging has to be evaluated in further studies.The authors declare that they have no competing interests.EH carried out CMR examinations, image analysis and drafted the manuscript. KL and SS coordinated the study. HA, KF and SA participated in the study design. TE participated in the study design and strain analysis. HJS participated in the study design and CMR analysis. All authors have made revisions to the manuscript and have read and approved the final version.


Heart transplantation (HTX) is an established life-saving treatment for patients with end-stage heart failure. However, several injuries can compromise cardiac allograft function over the years after HTX, i.e. organ rejection, transplant vasculopathy or infections which can lead to myocardial fibrosis, cardiac remodeling and ventricular dysfunction. Non-invasive late gadolinium contrast enhanced MRI (LGE-CMR) is able to identify myocardial tissue alterations as well as morphological and functional changes. To date, no longitudinal follow-up CMR data on myocardial function and tissue characterization exists on patients after HTX. Therefore, we sought to evaluate longitudinally functional and morphological changes after HTX employing non-invasive LGE-CMR.61 HTX patients were included in the study and were scanned twice after HTX  only for CAV0 and CAV3 but not for intermediate lesions (CAV1/2, Figure The increase of both infarct-typical and -atypical LGE patterns after HTX can be considered as a result of several injuries over the years after HTX. The lack of changes in cardiac morphology and function may be explained by the strict surveillance and early treatment of organ rejection, infections and the advances in the immunosuppressive therapy.none


Systemic sclerosis (SSc) is associated with an increased risk of developing pulmonary fibrosis or pulmonary arterial hypertension. Pulmonary arteriolar proliferation in SSc might yield a reduction in the pulmonary blood density (PBD). However, we hypothesized that PBD would be increased in SSc due to increased pulmonary artery pressure and distension.We aimed to use cardiovascular magnetic resonance imaging (CMR) to explore the pulmonary blood volume (PBV), the PBV variation over the cardiac cycle (PBVV), and the PBD as possible measures of pulmonary involvement in newly diagnosed SSc.Twenty-seven SSc patients  and 20 healthy subjects  underwent CMR. The PBV was calculated as the product of cardiac output determined by velocity encoded CMR, and the pulmonary transit time determined as the time for a 2 ml intravenously administered contrast bolus to pass from the pulmonary trunk to the left atrium, as previously validated. The lung volume was determined by planimetry using transversal MR images covering the lungs. The PBD was defined as the PBV divided by the lung volume. Also, the blood flow in the pulmonary artery and the pulmonary veins was measured using velocity encoded CMR. The PBVV was calculated by integration of the difference in arterial and venous pulmonary flow over the cardiac cycle.Compared to healthy subjects, SSc patients had lower PBV , lower PBD  had PBD below normal limits), but no difference in PBVV/stroke volume . PBD correlated with Doppler echocardiography estimated pulmonary artery pressure  and the diffusion capacity for carbon monoxide (DLCO) in the lungs , but was not affected by pulmonary fibrosis by high-resolution computed tomography (p=0.34).Compared to healthy subjects, newly diagnosed SSc patients have a reduced amount of blood in the pulmonary vasculature (PBD), and PBD is inversely related to pulmonary artery pressure. The findings are consistent with an involvement of pulmonary arterioles in SSc. Also, this is the first human study to quantify the pulmonary blood density by CMR. Further studies are justified to assess the utility of PBD as a diagnostic and prognostic measure of pathophysiological changes in cardiopulmonary disease.