Cardiac MRI is used to measure right ventricular end diastolic volume indexed to body surface area (RVEDVi) and ejection fraction (EF) in the setting of pulmonary insufficiency (PI). There is data describing optimum RVEDVi, in tetralogy of fallot (TOF) patients, to provide a competent pulmonary valve and maintain long term RV function. Pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (CPS) are congenital heart defects with variable right ventricle (RV) morphology including severe hypoplasia. A subset of these patients undergo initial palliation with right ventricular outflow tract reconstruction to allow for antegrade flow across the pulmonary valve and PI to encourage RV growth over time. There is limited RV volumetric and function data to guide pulmonary valve replacement in this population. The lack of data concerning RV growth in this population may lead to mistimed valve replacement such that RV systolic or diastolic function is permanently compromised. Hypothesis: RVEDVi growth will be different between patients with TOF and PAIVS/CPS; and systolic function will be decreased at equivalent volumes in the PAIVS/critical PS group.Two groups of patients were studied for RV size by MRI volumetric measurement: Group 1 were patients with TOF s/p repair and residual PI, Group 2 was comprised of patients with PAIVS or CPS with HRV who underwent RVOT reconstruction. MRI was performed on GE or Philips 1.5T scanners at Children's Hospital Los Angeles. Short axis cine images were analyzed for RV and LV size. Phase contrast imaging was used to assess flow in the main and branch pulmonary arteries to determine regurgitant fraction. Student's T-test or Wilcoxon Rank Sum tests were used to compare age, height, weight, BSA, RV and LV sizes between the two groups. Linear regression was performed with the model RVEDVi vs. age at time. Multivariate regression was performed with the outcome variable RVEF.114 patients with TOF and 25 patients with PA/IVS-CPS had data reviewed spanning a period of 14 years. The groups were well matched for height, weight and BSA, while there was a trend toward younger age in the PAIVS group (P = 0.06). The RVEDVi, RVESVi and RVEF of patients with PA/IVS-CPS and TOF were not significantly different . RVEDVi was plotted against age and there was no difference in slope of the regression lines, suggesting similar growth of the RV between PAIVS-CPS and TOF, which was consistent with limited longitudinal data (Figure RV growth and systolic function is similar between a PA/IVS-critical PS group and TOF group after RV outflow tract reconstruction. There is significant RV:LV interaction driving RV systolic function in both groups.There was no funding support for this study.


Cardiovascular magnetic resonance (CMR) is an integral part in the diagnostic work-up of cardiac inflammatory diseases. In this context, superparamagnetic iron oxide-based contrast agents can provide additional diagnostic information regarding the assessment of myocardial infarction and myocarditis. After intravenous administration, these nanoparticles are taken up by activated monocytes and macrophages, which predominantly accumulate in regions associated with inflammation as was successfully shown in recent preclinical studies. Furthermore, first clinical studies with a new iron oxide-complex that was clinically approved for the treatment of iron deficiency anaemia recently demonstrated a superior diagnostic value of iron oxide nanoparticles compared to gadolinium-based compounds for imaging of myocardial inflammation in patients with acute myocardial infarction. In this article, we outline the basic features of superparamagnetic iron oxide-based contrast agents and review recent studies using such nanoparticles for cardiac imaging in case of acute myocardial infarction as well as acute myocarditis. Moreover, we highlight the translational potential of these agents and possible research applications with regard to imaging and therapy. Myocardial inflammation is associated with a broad spectrum of pathophysiological pathways and may eventually cause both severe structural and functional impairment of the heart muscle. In principle, myocardial inflammation can be triggered by various stimuli – including myocardial infections caused by pathogens such as viruses – and myocardial ischemia due to coronary artery occlusion in case of acute myocardial infarction. Such mechanisms may lead to myocardial necrosis and initiate subsequent appropriate as well as inadequate or excessive responses of the innate immune system. Adequate activation of the immune system may promote (amongst others) removal of dead cells and matrix debris. By contrast, an excessive inflammatory response may result in adverse changes of the geometry, function and structure of heart tissue, referred to as adverse remodelling , 2. A deCardiovascular magnetic resonance (CMR) is a well-established technique in the diagnosis of cardiovascular diseases. So far, non-invasive work-up of myocardial inflammation with CMR is mainly based on observing alterations in myocardial tissue composition . CMR pulNanoscaled particles with an iron oxide core and a polymer shell have been under investigation for the last two to three decades due to their versatile features. Probably most important, IONs exhibit superparamagnetic properties below a certain particle size. As a result, they show a much larger magnetic susceptibility than paramagnetic agents. However, they lose their magnetization in the absence of an applied magnetic field – in contrast to paramagnetic agents. An attractive feature of IONs is that, depending on their size and composition of their polymer shell, they are biocompatible and may form stable colloidal suspensions, which are equally important prerequisites for successful in vivo applications Fig. . After i3O4) and/or maghemite (γ-Fe2O3). These are organized in a crystalline pattern, which is controlled by the synthesis procedure just as the core’s composition [Although IONs may differ vastly according to their desired application (see above), they share a common structure. Briefly, they are composed of a magnetic core and a non-magnetic coating. The core consists of nanometre sized, monodispersed iron oxide particles of magnetite  and ferric (Fe3+) salts in an aqueous medium with the pH adjusted [Numerous synthesis pathways focusing on good reproducibility and the desired combination of core and coating have been examined. According to Laurent et al. the simplest and most efficient protocols involve co-precipitation techniques of ferrous . In general, when comparing the same particle doses, the effect of contrast enhancement is higher for IONs than for gadolinium-based contrast agents .The main factors determining pharmacokinetics and organ distribution of IONs are the biophysical characteristics and their surface chemistry such as composition, density and charge . DependiCellular uptake of IONs is primarily associated with phagocytosis. According to Weissleder et al. most dextran-coated IONs are phagocytosed by circulating monocytes or tissue resident macrophages . Due to Internalization of IONs results in a decreased blood circulation time, limiting the likelihood to reach the desired/targeted tissue or organ. Several strategies to prolong their blood half-life or to hide them towards cells of the RES have been discussed in the literature. In principle, particles possessing the following properties have shown a relatively increased blood circulation time: (i) hydrophilic coatings, (ii) hydrodynamic diameters smaller than 50 nm, (iii) neutral or near neutral charged surface designs and (iv) shielding groups added to the surface such as PEG that block electrostatic or hydrophobic interactions between opsonins and particle surface , 25, 38.Apart from imaging purposes, IONs can also be used as targeted carriers for drugs or small molecules. Due to their large surface-to-volume ratio, IONs enable the integration of multiple functional groups using appropriate surface chemistry . As reviBesides active targeting via functional groups, IONs can also accumulate at targeted organs/tissues by the help of an external magnetic field –43. ExplMechanisms leading to cellular damage or impairment of cellular viability are primarily related to surface chemistry and functionalization of the IONs. In this context, cellular uptake and subsequent degradation of the IONs have to be considered. According to Singh et al. cell exposure to IONs could theoretically induce toxic side effects such as impaired mitochondrial function, activation of inflammatory or apoptotic pathways with formation of apoptotic bodies, generation of reactive oxygen species and even DNA damage , 45. HowA major goal of performing ceCMR after myocardial infarction (MI) is to differentiate injured from (remote) healthy myocardium. In this context, Chapon et al. evaluated dextran-coated USPIOs in a rodent model of permanent ligation of the left coronary artery (LCA). Concentrations of 5 and 10 mg Fe/kg were administered once after 5 h, 24 h and 48 h of occlusion followed by T2-weighted MR acquisitions. Subsequent image analysis revealed higher contrast between healthy and ischemic myocardium in series acquired at later stages. Furthermore, these authors identified a negative linear relationship between contrast enhancement and the elapsed time since induction of MI. However, doubling the concentrations of IONs did not significantly increase the observed contrast .Since macrophages are primarily involved in the regulation of post-MI wound healing, Sosnovik and colleagues studied the infiltration of macrophages in the infarcted tissue. Permanent ligation of the LCA was performed in mice followed by the administration of varying concentrations of a magnetofluorescent USPIO. Forty-eight hours after ION injection, T2-weighted CMR of the myocardium showed a negative contrast enhancement in the left ventricular (LV) anterior and adjacent walls – that was not observed in sham mice. Calculated contrast-to-noise-ratio (CNR) between remote  myocardium and injured LV wall segments was significantly higher for mice treated with USPIOs. Moreover, average CNR increased with increasing ION concentration. Since these findings were confirmed by ex vivo immunohistochemistry , the authors concluded that visualization of labelled macrophages is feasible in vivo and allows the assessment of myocardial injuries after infarction .In contrast to the aforementioned studies, Montet-Abou et al. investigated labelling of resting monocytes and macrophages prior to occlusion-reperfusion of the left anterior descending artery (LAD). Labelling was aimed at with polymer-coated VSPIOs that were administered to rats three days prior to LAD occlusion. This duration was chosen in order to ensure total clearance of VSPIOs from the blood pool. Following reperfusion, T2-weighted CMR was repeated every 24 h. In doing so, hypointense areas indicative of infarcted myocardium were only visible in rats treated with IONs. Additional mapping of T2-values revealed an increase in signal void (negative enhancement) over elapsed time since reperfusion. This temporal signal change was consistent with an increasing number of pre-loaded monocytes and macrophages found in infarcted tissues by histology. Additional MR-tagging studies showed a relationship between hypointense areas and hypokinetic segments. In summary, the authors could demonstrate that pre-loading and subsequent tracking of ION-labelled macrophages is suitable to depict changes in infarct-associated inflammatory diseases .In a recent study, Protti et al. extensively investigated the performance of VSPIOs in a murine model of ischemia-reperfusion . The IONTo the best of our knowledge, there is only one pre-clinical animal study published so far that addresses ION-administration and CMR of inflammatory processes associated with myocarditis: In 2012, Moon and colleagues presented the results of their comprehensive rodent study, examining the feasibility to detect and discriminate different grades of experimental autoimmune myocarditis (EAM) by the help of SPIOs. They used IONs covered by a fluorophore-incorporated silica coating that were additionally conjugated with PEG polymer chains. Experimental setups involved injection of 10 mg Fe/kg on day 21 after induction of EAM or 24 h before CMR, respectively. Histological examinations comprising different staining and microscopy techniques were performed after imaging . First, To evaluate in vivo assessment of EAM using SPIO-based ceCMR, Moon and collaborators determined the CNR of the LV septum between pre- and post-SPIO images. T2-weighted images acquired 30 min after injection of SPIOs showed homogenous negative contrast enhancement in ventricle walls of both EAM and control rats indicating SPIO accumulation. Consequently, CNR was significantly decreased. While contrast normalized after 24 h in the control group, areas of negative contrast enhancement persisted in EAM rats. In accordance to histological findings, the authors assumed that IONs were present in the vasculature after the injection in both groups, but were washed-out from site afterwards in control rats. Further, they presume that inflammatory cells including macrophages infiltrated affected tissue and phagocytosed SPIOs preventing their washout in rodents infected with EAM .To evaluate the diagnostic yield of SPIO-based ceCMR regarding discrimination of histologically defined grades of myocardial inflammation, CMR was performed at different days after induction of EAM. A linear relationship was found between changes in CNR and stained areas of both inflammation and macrophage counts for all grades. However, the authors did not observe a significant difference in CNR between moderate and severe forms of EAM .In another experimental setup, the distinctiveness of SPIO-based ceCMR was compared to T2-weighted images as well as to early (EGE) and late-gadolinium-enhanced (LGE) CMR. All images were acquired sequentially including SPIO-based ceCMR in the same rats. In doing so, gadolinium-based ceCMR showed large areas of inflammation, but no small foci that were visible in SPIO-based ceCMR Fig. . Since tAdditional studies addressed the issue of assessing the evolution/disease course of EAM. IONs were administered in the same rats at day 15 and 20, respectively, after the induction of EAM. At day 16, SPIO-based ceCMR showed several inflammatory spots with significantly decreased pre- vs. post-SPIO CNR. In comparison, different contrast patterns and areas that tended to have an even lower CNR were observed at day 21. Furthermore, repeated CMR studies of EAM-rats 24 h, 72 h and 120 h after SPIO application at day 18 showed no migration of labelled macrophages into the neighbouring myocardium .Although many preclinical studies in different animal models and with different IONs rather consistently demonstrated that non-invasive visualization of myocardial inflammation with CMR is possible and based on in vivo and/or ex vivo labelling of monocytes/macrophages Table , the numThe first clinical trial in patients with acute myocardial infarction (entitled NIMINI-1) was performed by our group using ferucarbotran, a SPIO approved at that time as Resovist® for a non-cardiac indication . Twenty However, the reasons for this disappointing result were quite obvious: There is a linear relationship between the applied dose of U/SPIO and the degree of induced hypoenhancement in T2-/T2*-weighted images. The minimal concentration successfully used in animal models was 2-3 mg Fe/kg. Unfortunately, the approved dose of Resovist® (for patients with suspected liver disease) was one single injection of 1.4 ml Resovist® - corresponding to a dose of 39 mg Fe per patient. Due to medicolegal reasons, our group was not allowed to use a different dose at that time. Thus, the maximal Fe concentration after administration of Resovist® (e.g. in a 60 kg patient) was only 0.65 mg Fe/kg. Moreover, Resovist®’s blood half-life was possibly too short (<15 min) for efficient uptake in macrophages and accumulation in the infarcted myocardium.Recently, the group of Newby and co-workers from Edinburgh and our group independently (and at the same time) performed new clinical trials in patients with acute STEMI using for the first time ferumoxytol, an USPIO that was approved by the FDA for treatment of anaemia in patients with renal disease. The group from Edinburgh studied 10 patients (and 6 controls) and used a ferumoxytol concentration of 4 mg Fe/kg. CMR scans comprising T2*-weighted sequences were performed on a 3-T scanner within five days of admission at baseline, 24 h and 48 h and R2* values were calculated for specific regions of interest. In regions with infarcted myocardium, the R2* value increased from 41.0 ± 12.0 s(−1) at baseline to 155 ± 45.0 s(−1) (p < 0.001) at 24 h and to 124 ± 35.0 s(−1) (p < 0.05) at 48 h. Interestingly, a similar, however, lower change in R2* was documented in the remote (non-infarcted) myocardium while no change at all was detected in the skeletal muscle in this study .Our clinical phase-III trial with ferumoxytol (entitled NIMINI-2) comprised 14 patients with acute STEMI. After a first baseline CMR study (pre-USPIO) on a 1.5-T scanner, a follow-up CMR study (post-USPIO) was performed 48 h after administration of ferumoxytol. In this trial, the approved dose of ferumoxytol (containing 510 mg Fe in 17 ml solution) was used - resulting in a concentration of e.g. 8.5 mg Fe/kg in a 60 kg subject - while the median dose of iron was 5.4 mg Fe/kg in the NIMINI-2 study. The median extent of T2-weighted hypoenhancement in the region of myocardial infarction - which was not present in baseline studies in any patient (!) - was 19% (IQR 14-22%)  and started to launch Rienso® across Europe. Unfortunately, Rienso® is no longer marketed in Europe due to commercial reasons. Moreover, since ferumoxytol is not renally eliminated, it can also be safely administered to patients with severe renal dysfunction – in contrast to gadolinium-based compounds.Compared to ferucarbotran (an SPIO that was used in the NIMINI-1 study), ferumoxytol is an USPIO with a mean diameter of only ~30 nm, a neutral surface charge, a magnetic relaxivity of r1 = 15 mmol/L/s and r2 = 89 mmol/L/s (at 1.5 T) and a blood half-life of ~15 h. Such a long blood half-life that is due to its small size and neutral surface charge is a prerequisite for accumulation of such particles (during continuous blood circulation) in the inflamed/infarcted myocardium. Although ferumoxytol is not approved as an CMR contrast agent so far, the specific magnetic relaxivity properties of ferumoxytol do allow both T1-weighted as well as T2-/T2*-weighted MR imaging – as was shown in the NIMINI-2 study. Noteworthy, ferumoxytol was developed by AMAG Pharmaceuticals, Inc., in the USA and was first approved as FerahemeFrom a clinical point-of-view, the opportunity to image/visualize infiltrating macrophages in the inflamed myocardium will be of potential diagnostic as well as therapeutic value since the extent and degree of myocardial disease might be monitored more accurately and therapeutic success might be assessed more appropriately. Moreover, USPIOs such as ferumoxytol may help to differentiate acute myocardial inflammation from rather chronic myocardial disease  – which is not possible with current conventional gadolinium-based approaches. In this context, future applications of USPIO may also comprise other cardiac diseases that are characterised by myocardial inflammation such as cardiac transplant rejection or cardiac sarcoidosis.−) that primarily remove necrotic cells and debris, and a second resolution phase (following day ~4 after acute MI) in which reparative monocytes (CD16+) predominate and orchestrate myocardial tissue repair. In addition, recent preclinical studies suggest that a misbalance between these two phases (e.g. an excessive accumulation of inflammatory monocytes during the first phase) may have adverse effects on infarct healing [Recently, two distinct phases in the process of infarct healing were described : a first healing . TherefoMoreover, it has to be expected that monocyte/macrophage trafficking in case of non-ischemic inflammatory diseases such as myocarditis will show different patterns of monocyte/macrophage activation with different cell subsets being involved. Hence, the affinity of IONs to monocytes/macrophages involved in acute (human) myocarditis might be different compared to those ones orchestrating inflammation in case of myocardial infarction. Future clinical studies with comprehensive myocardial tissue as well as blood analyses will hopefully allow evaluating such sophisticated differences.Although (passive) uptake of IONs by infiltrating monocytes/macrophages seems to be the major mechanism leading to myocardial signal void on T2-/T2*-weighted CMR images, the pre-clinical data of Protti et al.  as well Finally, the versatile coating properties of USPIOs in addition to the possibility to navigate such particles to the targeted organ/tissue by using external permanent magnets, make these particles highly suitable as versatile drug-carriers for targeted therapy. Since stem cell transplantation is a promising strategy for therapy of acute myocardial infarction and of CAD-driven heart failure, USPIO may also be used to label, target and subsequently visualize such cells in vivo using CMR. Recently, Cheng et al.  performe


Intramyocardial hemorrhage (IMH) identified by CMR is an established prognostic marker following acute myocardial infarction (AMI), but remains relatively underused in the clinical setting. Detection of IMH by T2-weighted or T2* CMR can be limited by long breath hold times and sensitivity to artefacts, especially at 3 Tesla. Alternative methods that can detect IMH with shorter breath hold times are therefore desirable. CMR is capable of detecting differences in the magnetic susceptibility of tissues. The paramagnetic properties of hemoglobin products within IMH cause local phase shifts relative to surrounding tissue. Phase data can be filtered and combined with magnitude data to generate susceptibility weighted MR images (SW MRI). SW imaging has been shown to be highly sensitive for the detection of cerebral hemorrhage, but typically uses long echo times, resulting in prolonged image acquisition. With the larger size of IMH, we hypothesized that SW MRI may be used with shorter echo times, leading to rapid imaging with breath hold times of approximately 4 seconds. We compared the image quality and diagnostic ability of this SW MRI pulse sequence with T2-weighted and T2* CMR to detect IMH at 3T.Forty-nine patients  underwent 3T CMR 2 days following reperfused AMI. T2-weighted, T2* and SW MRI images were obtained. Example images are shown in Figure κ = 0.90 and κ = 0.88 respectively); both had higher reliability than T2* (κ = 0.53). Intra-observer reliability was κ = 0.79, κ = 0.79 and κ = 0.74 respectively for SW MRI, T2w and T2* imaging. Breath hold times were shorter for SW MRI (4 seconds vs. 16 seconds) with improved image quality rating .Of 49 patients, IMH was detected in 20 (41%) by SW MRI, 21 (43%) by T2-weighted and 17 (34%) by T2 star imaging (p=ns). Contrast to noise measurements were similar between the three sequences . Compared to T2-weighted imaging, SW MRI had sensitivity of 93% and specificity of 86%. SW MRI had similar inter-observer reliability to T2-weighted imaging . DMH is an employee of Philips.


Appropriate fluid management is one of the most important elements of early goal-directed therapy after cardiothoracic surgery. Reliable determination of fluid responsivenss remains the fundamental issue in volume therapy.The purpose of the study was to assess the usefulness of dynamic IVC-derived parameters  in comparison to passive leg raising, in postoperative fluid management in mechanically ventilated patients with left ventricular ejection fraction ≥ 30 %, immediately after elective coronary artery bypass grafting.Prospective observational case series study including 35 patients with LVEF ≥ 30 %, undergoingelective coronary artery bypass grafting was conducted. Transthoracic echocardiography, passive leg raising and intravenous administration of saline were performed in all study subjects. Dynamic parameters derived from ultrasonographic assessment of the IVC diameter (collapsibility index–CI and distensibility index–DI), cardiac outputThere were 24 (68.57 %) responders in the study population. There were no statistical differences between the groups in relation to: clinical parameters, pre- and postoperative LVEF, fluid balance and CVP. Change in cardiac output after passive leg raising correlated significantly with that after the volume expansion . Dynamic IVC derivatives were slightly higher in fluid responders, however this trend did not reach statistical significance. None of the caval indices correlated with fluid responsiveness.Dynamic IVC-derived parameters do not predict fluid responsiveness in mechanically ventilated patients with preserved ejection fraction immediately after elective coronary artery bypass grafting. Passive leg raising is not inferior to volume expansion in differentiating between fluid responders and nonresponders. Immediate fluid challenge after CABG is safe and well tolerated.The online version of this article (doi:10.1186/s12947-016-0065-4) contains supplementary material, which is available to authorized users. Postoperative goal-directed therapy has been shown to substantially improve clinical outcomes in surgical patients , 2. Two Among the numerous monitoring methods, ultrasonographic measurement of inferior vena cava (IVC) diameter respiratory variation seems to meet the criteria of an ideal bedside tool to assess the individual fluid responsiveness. However, this method has been validated in selected populations  or healthy volunteers, and its usefulness has not been confirmed in patients after cardiac surgery –15. In oThe purpose of the present study was to assess the usefulness of dynamic IVC-derived parameters  in comparison to passive leg raising, in postoperative fluid management in mechanically ventilated patients with left ventricular ejection fraction ≥30 %, immediately after elective coronary artery bypass grafting.2O).The study population consisted of 35 consecutive adult patients admitted to our hospital for elective coronary artery bypass grafting. Exclusion criteria were: age <18 years, preoperative left ventricular ejection fraction (LVEF) <30 %, preoperative left ventricular dilatation (end-diastolic dimension ≥6 cm), preoperative severe tricuspid valve regurgitation, preoperative right ventricular dysfunction (tricuspid annular plane systolic excursion <16 mm), at least moderate aortic valve disease, at least moderate mitral valve disease and difficult acoustic window resulting in inability to obtain interpretable ultrasound images. Coronary artery bypass grafting was performed using cardiopulmonary bypass. In all patients full midline sternotomy was made. Mediastinal drainage (midline drain tubes) was placed in all patients. Additionally, those with arterial graft with left internal mammary artery had a drain placed in left pleural cavity. All patients were operated in moderate hypothermia (32–33 °C) and warmed up to 36.6 °C within two hours following the end of the operation. Total intravenous anesthesia with propofol, sufentanil and pancuronium was used during the procedure. Propofol infusion was continued for 1-hour in the ICU and morphine infusion was used for postoperative pain relief. Cardiac ultrasound was performed when the patients were ventilated , gender, weight (kg), height (cm), number of bypassed vessels, aortic cross-clamping duration, cardiopulmonary bypass duration, and preoperative echocardiographic parameters . Pulse pressure was calculated as the difference between systolic and diastolic pressure readings (expressed in mmHg). The use of the following vasoactive drugs was noted: nitroglycerine, dopamine, dobutamine, epinephrine, norepinephrine.Transthoracic bedside echocardiography was performed by two trained investigators, both with at least 5 years of experience in emergency ultrasound. The examinations were conducted with portable ultrasound system equipped with a 1–5 MHz transthoracic phased-array transducer . All the studies were recorded as digital clips and reviewed independently by both sonohraphers.Inferior vena cava was visualized longitudinally in the subcostal view. Maximal and minimal IVC diameters  were measured using 2D image, distally to the hepatic vein inlet, over a single respiratory cycle. A total of three measurements were obtained and averaged for each IVC diameter. The IVC collapsibility index (IVC-CI) was defined as: IVC-CI = IVCmax - IVCmin/IVCmax. The IVC distensibility index (IVC-DI) was calculated using the formula: IVC-DI = IVCmax - IVCmin/IVCmin. Both indices were expressed as a percentage.2 x VTI LVOT x HR. The left ventricular outflow tract diameter (dLVOT) was measured in midsystole, in a parasternal long-axis view immediately adjacent to the aortic valve. LVOT velocity time integral (LVOT VTI) was recorded by pulsed Doppler imaging from a three-chamber or five-chamber apical view. Left ventricular ejection fraction (LVEF) was assessed by visual inspection.Cardiac output (CO) was calculated from the left ventricular outflow tract (LVOT), using the previously described equation : CO = 0.Hemodynamic and ultrasound data were obtained at four sequential steps per enrollment: (1) at baseline, immediately after cardiac surgery procedure, when the patient was transferred to intensive care unit, in the semirecumbent position (45 °); (2) during passive leg raising (after 1 min), when the patient’s lower limbs were raised to a 45 ° angle while the patient’s trunk was lowered in supine position; (3) in the semirecumbent position (as a baseline data for the next stage); (4) after a 10-min infusion of 250 ml of saline, in the semirecumbent position. Fluid balance immediately after cardiac surgery was noted. The following parameters were recorded at each study step: heart rate , systolic blood pressure , diastolic blood pressure , central venous pressure , maximal  and minimal  diameters of inferior vena cava, left ventricular ejection fraction , velocity time integral in left ventricular outflow tract . Fluid responsiveness was defined as an increase in cardiac output ≥15 % after the fluid challenge that defined patients as responders and non-responders. Any clinically significant findings  were immediately reported to the treating physician.Statistical analysis was performed using STATISTICA v 8.0 software. The required size of the study group was determined with power analysis. Using prior estimates of expected correlation, a sample size of 9 for each subgroup (responders and nonresponders) was determined, with α = 0.05 and β = 0.8. Numerical data were expressed as mean values ± SD. After determining the probability distribution with Shapiro-Wilk test, the comparisons between fluid responders and nonresponders were performed with U Mann–Whitney test. A p-value of 0.05 was considered significant. The correlations between different parameters were evaluated with r-Spearman correlation analysis. Scatterplots for the two variables were drawn with confidence interval 0.95. The area under the receiver operator characteristics curve (AUROC) was used to determine the diagnostic accuracy of the methods.p = 0.000, r = 0.822) . The general diagnostic accuracy of IVC-DI (AUROC) was 0.647. When using the value of 18 % (according to the literature) as a cut-off point distinguishing responders form nonresponders, the AUROC increased to 0.739. IVC-DI of ≥18 % had sensitivity of 82.35 % and specificity of 72.72 % in predicting a 15 % increase in cardiac output after fluid administration.The study population consisted of 35 consecutive patients  who underwent elective coronary artery bypass grafting Additional file This prospective observational case series was designed to test the effectiveness of IVC-derived parameters in predicting fluid responsiveness immediately after elective coronary artery bypass grafting. Our previous study did not confirm the utility of caval indices as a guiding tool for early postoperative fluid therapy in a heterogeneous group after cardiac surgery . The preThe majority of patients in our study  responded to fluid challenge with significant cardiac output increase and met the criteria of fluid responsiveness. While we excluded patients with severely impaired left ventricular systolic function and LV dilatation, the main contributor of stroke volume increase were preload conditions. It seems that response to fluid challenge was mainly determined by absolute  and relative hypovolemia . In our study fluid challenge with 250 ml of saline/PLR was safe and well tolerated in all subjects. Considering our results, we assume that immediate administration of crystalloids directly after CABG regardless hemodynamic parameters is reasonable, low-risk profile management.Ultrasonographic measurement of IVC respiratory variation did not reach statistical significance in differentiation between fluid responders and nonresponders. Although we observed a trend towards higher values of both IVC indices (IVC-CI and IVC-DI) in responder group, none of them was statistically significant. In our study material we observed high variation of recorded measurements with overlapping series of values. Thus, it was impossible to determine a cut-off point separating responders and nonresponders.Ultrasonographic assessment of the inferior vena cava diameter has been proposed as a bedside, noninvasive marker of fluid status . The use2O) may contribute to negative results of this paper. However very attractive, ultrasonographic definition of fluid responsiveness using IVC respiratory variation failed in early postoperative period after cardiothoracic surgery that was also described in our previous work [There are multiple possible reasons contributing to limited usefulness of dynamic IVC derivatives in early postoperative period after CABG . First oous work .p = 0.000, r = 0.822). A 15 % PLR-induced increase of cardiac output predicted the corresponding increase in cardiac output after fluid administration with 79.17 % sensitivity and 81.82 % specificity. These results are in concordance with available literature. Monnet et al. [Several diagnostic approaches have been tested to determine fluid responsiveness in mechanically ventilated patients. Respiration-induced changes in arterial pulse pressure (ΔPP), based on the variation in arterial pressure associated with mechanical ventilation, have been demonstrated to accurately predict fluid responsiveness in mechanically ventilated patients with regular heart rhythm, who are making no respiratory efforts . Howevert et al.  proved tt et al.  demonstrt et al. , PLR-indt et al. , also det et al. . The AURReliable, real time measurement of stroke volume  remains the key issue in determination of fluid responsiveness . The theWe conclude that dynamic IVC-derived caval index does not predict fluid responsiveness in mechanically ventilated patients with preserved LVEF immediately after elective coronary artery bypass grafting. Passive leg raising is not inferior to intravenous volume expansion in differentiating between fluid responders and nonresponders. Immediate fluid challenge after CABG is safe and well tolerated.AUROC, area under the receiver operator characteristics curve; CABG, coronary artery bypass grafting; CVP, central venous pressure; DBP, diastolic blood pressure; HR, heart rate; ICU, intensive care unit; IVC-CI, inferior vena cava collapsibility index; IVC-DI, inferior vena cava distensibility index; IVC, inferior vena cava; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; MAP, mean blood pressure; PAC, pulmonary artery catheter; PLR, passive leg raising, PP-pulse pressure; SBP, systolic blood pressure; SD, standard deviation; VTI, velocity-time integral


Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS . However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs  and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd , and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs  and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can be reversed. Furthermore, in the early stages of recovery, cardiac remodeling may be intensified. Finally, compared with the LV, the RV is not as easily reversed. Cardiac remodeling pathways, such as, HDAC4, ERK1/2, LC3-II, and AMPK were involved in the process. There are various changes in the human cardiovascular system, including a cephalic fluid shift  is a suitable model. There is extensive literature investigating the cardiovascular adaptation to simulated microgravity, predominantly using the HU rat or mouse model . We determined that pathological remodeling signals are overactive in both the LV and RV following HU and/or HR, and are restored after 14 days of reloading. The physiological remodeling signal AMPK is downregulated in both the LV and RV, which leads to the functional decline of both ventricles. Finally, we found that recovery is more difficult in the RV than the LV. This study provides insight into the molecular mechanisms of cardiac remodeling and the decline of systolic function of both the LV and RV during simulated microgravity and recovery.All mice used in the experiments were bred and maintained at the SPF Animal Research Building of China Astronaut Research and Training Center . The mice used on this study were 3 month old males and in a C57BL/6N background. The experimental procedures were approved by the Animal Care and Use Committee of China Astronaut Research and Training Center, and all animal studies were performed according to approved guidelines for the use and care of live animals.The hindlimb-unloading procedure was achieved by tail suspension, as described by Morey-Holton and Globus . BrieflySections were generated from paraffin embedded hearts, and were stained with H&E for gross morphology, Masson's trichrome for detection of fibrosis, as described before Ling et al. .Gapdh, which served as an internal control. Primers  for Col1a1 , Col3a1 , BNP , and Gapdh , were as follows:Col1a1 sense primer: 5′-CTG ACTGGAAGAGCGGAGAGT-3′,Col1a1 anti-sense primer: 5′-AGA CGGCTGAGTAGGGAACAC-3′;Col3a1 sense primer: 5′-ACG TAAGCACTGGTGGACAG-3′,Col3a1 anti-sense primer: 5′- CAGGAGGGCCATAGCTGAAC-3′;BNP sense primer: 5′-TGT TTCTGCTTTTCCTTTATCTG-3′,BNP anti-sense primer: 5′-TCT TTTTGGGTGTTCTTTTGTGA-3′;Gapdh sense primer: 5′-ACT CCACTCACGGCAAATTCA-3′,Gapdh anti-sense primer: 5′-GGC CTCACCCCATTTGATG-3′.Total RNA was extracted from heart tissues by using RNAiso Plus reagent (Takara) according to the manufacturer's protocol. The RNA (500 ng/sample) was reverse transcribed into cDNA and qPCR was performed using a SYBR Green PCR kit (Takara) in a Light Cycler . PCR for each sample was carried out in duplicate for all cDNAs. The mRNA level of each gene was normalized to that of Animals were lightly anesthetized with 2,2,2-tribromoethanol (0.2 ml/10 g body weight of a 1.2% solution) and set in a supine position. Two dimensional (2D) guided M-mode echocardiography was performed using a high resolution imaging system . Two-dimensional images are recorded in parasternal long- and short-axis projections with guided M-mode recordings at the midventricular level in both views. Left ventricular (LV) cavity size and wall thickness are measured in at least three beats from each projection. Averaged LV wall thickness [interventricular septum (IVS) and posterior wall (PW) thickness] and internal dimensions at diastole and systole  are measured. LV fractional shortening ((LVIDd – LVIDs)/LVIDd), relative wall thickness [(IVS thickness + PW thickness)/LVIDd], and LV mass [LV Mass = 1.053 × [(LVIDd + LVPWd + IVSd)3 – LVIDd3]] are calculated from the M-mode measurements. LV ejection fraction (EF) was calculated from the LV cross-sectional area (2-D short-axis view) using the equation LV %EF = (LV Vold – LV Vols)/LV Vold × 100%. For RV, Two-dimensional images are recorded in right parasternal long- and short-axis projections with guided M-mode recordings at the maximum diameter level in both views. Right ventricular (RV) cavity size and wall thickness are measured in at least three beats from each projection. Averaged Right Ventricle Anterior Wall and internal dimensions at diastole and systole  are measured. Right Ventricle Percent Fractional Shortening (RVIDd – RVIDs)/RVIDd × 100%). Right Ventricle Percent Ejection Fraction (EF) was calculated from the RV cross-sectional area (2-D short-axis view) using the equation RV %EF = (RV Vold – RV Vols)/RV Vold × 100%.For the RV mass weight calculation, firstly, we measured the RV endocardial borders in diastole (five measures) and systole (five measures) in five consecutive cardiac cycles in each flat-image, generating 10 RV endocardial areas (RVendo). Then, we got the epicardial borders and corresponding RV epicardial areas (RVepi) on the same frames. Ten RV free wall areas were then calculated by subtracting RVendo from RVepi (RVepi-RVendo). Finally, the total RV free wall volume of each plane was calculated by Simpson's method using the mean of the RV free wall area. RV free wall mass was obtained by multiplying this volume by the specific density of the myocardium (1.05 g/cc).Mouse hearts were crushed by homogenizer  and then lysed in lysis buffer  on ice for 15 min. Protein fractions were collected by centrifugation at 12,000 g at 4°C for 15 min and then applied to 8–12% SDS-PAGE gels, electrophoresed at 80 V fof 30 min and 120 V for 90 min. After electrophoresis, protein was transfected to a polyvinylidene fluoride membrane using a Criterion blotter apparatus (Bio Rad). The membrane was then blocked in 5% non-fat dry milk  in TBST  for 1 h. After that, the membrane was incubated with primary antibody overnight at 4°C followed by incubation with a secondary antibody conjugated to horseradish peroxidase (HRP), and visualized using an chemiluminescence kit . Specific antibodies to p-HDAC4 , HDAC4 , p-AMPKα , AMPKα , p-ERK1/2 , ERK1/2 , LC3-II/I , mTOR , p-mTOR  Atrogin1 , MuRF1 , Gapdh  were used to detect protein levels. Gapdh was used as a loading control.t-test for one-way analysis. Otherwise we use Student's t-test. Bonferroni adjustment was used for multiple comparisons. P < 0.05 is considered statistically significant. P < 0.01 is considered very significant. All the statistical tests are analyzed by Prism software .Data are presented as mean ± SEM per experimental condition. For the statistical differences among groups, considering the presence of unequal variance for the data, we firstly test the equality of variances across groups. If it shows the variances are unequal, we then use Welch's n = 10; HR-7d, n = 10; HR-14d, n = 10). The control group (n = 10) was treated equally, with the exception of tail suspension , and left ventricular ejection fraction (LV-EF) decreased significantly in HU mice compared with the control, and did not recover during the first few days of HR. Full recovery was only apparent after reloading for 14 days Figure . HoweverTo validate the influence of HU and HR in the LV, we performed transthoracic echocardiography to determine the structure of the LV following HU and HR Figure . CompareTo validate the influence of HU and HR in the RV, we performed transthoracic echocardiography to assess the structure and function of the RV following HU and HR Figure . After 2Col1a1, Col3a1, and BNP mRNA levels increased in the LV, and recovered, although not significantly  sections, gross evidence of edema was easily observed by separation of the myofibers in the LV, the interventricular septum (IVS), and the RV following HU. Recovery to a normal state occurred following 14 days of HR Figure . Masson y Figure . In the R Figure . These rTo gain more insight into the signaling pathways involved in the declining function of both the left and right ventricles, we examined several important signaling molecules involved in cardiac remodeling induced by external or intrinsic stimuli. As shown in Figure We also analyzed the changes of mTOR phosphorylation and MuRF1/Atrogin1 levels, which are involved in protein synthesis and degradation pathways, respectively. In LV, As is shown in Figure In this study, we report for the first time the differences between left and right ventricular remodeling induced by simulated microgravity and reloading. We also characterize the signaling molecules involved in this cardiac remodeling. Consistent with previous reports, our study indicates that left ventricular function declines following HU but recovers to its normal state after 14 days of reloading. Few studies have focused on the RV, however. We show here that the function of the RV also declines following HU, but does not recover even after 14 days of reloading. In other words, both the left and right ventricle exhibited a decline in function, but recovery of right ventricular function was much more difficult. We demonstrate that pathological remodeling signals, such as HDAC4, were activated following HU and recovered following HR in both the LV and RV. The physiological remodeling signal AMPK was inhibited in both the LV and RV following HU, but only restored in the LV following 14 days of HR.Several studies have suggested that microgravity or simulated microgravity lead to cardiac remodeling, and result in cardiac deconditioning when reloaded. In humans exposed to 6 weeks of bed rest, LV mass decreased by 8.0 ± 2.2%, RV free wall mass decreased by 10 ± 2.7%, and RV end-diastolic volume decreased by 16 ± 7.9%. After 10 days of spaceflight, LV mass decreased by 12 ± 6.9%. Thus, cardiac atrophy occurs during prolonged horizontal bed rest, but may also occur after short-term spaceflight  and the Grant of State Key Lab of Space Medicine Fundamentals and Application .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer [JA] and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review


Although several reports demonstrate the efficacy of stress echocardiography in diagnosing coronary artery disease, comparable studies on the competence of the same imaging technique at rest are limited. This study aimed to evaluate whether ventricular akinesia/hypokinesia and left ventricular ejection fraction (LVEF) < 55 % at rest are useful in predicting abnormal coronary angiography.This study prospectively enrolled 100 diagnostic coronary catheterization candidates. Any routine echocardiography that the candidates had undergone before diagnostic coronary catheterization was reviewed. Patients were subclassified according to the presence and location of ventricular akinesia/hypokinesia, LVEF, and the results of diagnostic coronary catheterization. LVEF < 55 % was considered below the normal physiological limit. Abnormal coronary angiography was defined as narrowing of half or more of the caliber of at least one major coronary artery.P = 0.002) and LVEF < 55 % . Screening of akinesia/hypokinesia and LVEF < 55 % as diagnostic tools for abnormal coronary angiography achieved comparable sensitivities (87.2 % vs. 88.9 %), specificities (41.5 vs. 41.8), and diagnostic accuracies (41.5 vs. 41.8). Left ventricular anterior wall akinesia/hypokinesia achieved a higher diagnostic odds ratio (9.7), sensitivity (95 %), and negative predictive value (96.4 %) compared with other types of akinesia/hypokinesia.Abnormal coronary angiography was significantly associated with akinesia/hypokinesia (OR = 4.85, The overall diagnostic accuracy of akinesia/hypokinesia and LVEF < 55 % to predict abnormal coronary angiography was poor, probably owing to significant influences of macro- as well as micro-vascular ischemia on left ventricular function. Myocardial ischemia is known to depress cardiac contractility . ReductiCardiac stress tests evaluate the possible ischemic electrocardiography (ECG) changes, depressed LVWM or LVEF while heart activity is increased by exercise or other inotropic factors , 10. AltThis study received clearance from the Ethics Review Committee of the Faculty of Medicine, Khartoum University, Sudan. Written informed consent was provided by each volunteer before being enrolled in the study.This study prospectively enrolled 100 diagnostic coronary catheterization (DCC) candidates in Al-Shaab Cardiac Center, Khartoum, Sudan. Following evaluation of sociodemographic characteristics, past medical history, and clinical examination of each patient, results of routine echocardiography conducted before DCC were reviewed. Patients were subclassified according to the presence and location of ventricular akinesia/hypokinesia, LVEF, and the results of DCC. The endocardial and epicardial motion, as well as thickening of each segment of the LV, were assessed to assign a wall motion score index (WMSI). Normal wall thickening (WMSI = 1) was considered indicative of normokinesia, while decreased (WMSI = 2) and absent (WMSI = 3) wall thickening were considered indicative of hypokinesia and akinesia respectively. Left ventricular anterior (LVAW), septal (LVSW), inferior (LVIW), and lateral (LVLW) walls were assessed for the presence of akinesia/hypokinesia, irrespective of which particular part of the wall was affected. According to the 16-LV segmentation model, LVSW included the basal anteroseptal, basal inferoseptal, mid-anteroseptal, mid-inferoseptal, and apical parts of the interventricular septum; LVAW included the basal, mid, or apical parts of the anterior LV wall; LVIW included the basal, mid, or apical parts of the inferior LV wall; and LVLW included the basal anterolateral, basal inferolateral, mid-anterolateral, mid-inferolateral, and apical parts of the lateral wall. LVEF < 55 % was considered to be below the normal physiological limit . Patientt-test was used to evaluate differences in the means of the studied variables between patients with normal coronary angiogram (NCA) and ACA. The binary logestic regression was used to evaluate the association between ACA and akinesia/hypokinesia as well as LVEF < 55 %. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy (DA), likelihood ratio of a positive test (LRP), likelihood ratio of a negative test (LRN), and diagnostic odds ratio (DOR) were calculated to evaluate akinesia/hypokinesia and LVEF < 55 % as screening tests for ACA. P < 0.05 was considered significant.Statistical analysis was performed using OpenEpi software, version 2.3, and Statistical Package for the Social Sciences (SPSS) for Windows, version 16.0 . Studied variables were described as the mean ± standard deviation. Proportions of the studied groups were expressed as percentages (%) and 95 % confidence intervals (CI). The unpaired 2) compared with those with NCA . ACA was significantly associated with male sex , diabetes mellitus , akinesia/hypokinesia . Eight of the subjects with NCA were male , and 53 of the subjects with ACA were male . Characteristics of the studied groups are given in Table Presence of LV akinesia/hypokinesia and/or LVEF < 55 % significantly increased the odds of having ACA in patients undergoing DCC. Currently, LVWM and LVEF are important indicators of LVF, and are commonly used to assess severity and prognosis of CAD . In one In the present study, the relatively higher sensitivity compared with specificity of akinesia/hypokinesia and LVEF < 55 % as screening tools for ACA suggests that these tests are more efficient in detecting, but not excluding, patients with ACA . The higAlthough it is evident from the current results and previous reports that abnormal LVWM and LVEF are common in CAD patients, the presence of such findings cannot exclude microvascular ischemia. The coexistence of angina and ischemic ECG changes with uneventful DCC in patients with NCA in the current study is highly suggestive of CSX in this group , 8. AccoThe current study had some limitations. Although 100 DCC candidates were enrolled, a larger sample size would have enabled more definitive conclusions to be made regarding the diagnostic accuracy of resting LV akinesia/hypokinesia in predicting ACA. In addition, the lack of stress echocardiography testing in Sudan precluded evaluation of LV akinesia/hypokinesia in the studied patients during increased heart activity. Combined evaluation of DCC patients with resting and stress echocardiography tests in the future could offer scientific evidence as to which test has better DA in predicting ACA.Evaluation of akinesia/hypokinesia and LVEF < 55 % as screening tools for CAD suggests that these tests were more reliable for detection, but not exclusion, of patients with ACA. Overall DA of these measures to discriminate ACA from NCA was poor, probably owing to the comparable influence of macro- and micro-vascular ischemia on LVF.∆LVEF, change in LVEF; ACA, abnormal coronary angiography; BMI, body mass index; CAD, coronary artery disease; CI, confidence intervals; CSX, cardiac syndrome X; DA, diagnostic accuracy; DBP, diastolic blood pressure; DCC, diagnostic coronary catheterization; DOR, diagnostic odds ratio; ECG, electrocardiography; LRN, likelihood ratio of a negative test; LRP, likelihood ratio of a positive test; LVAW, left ventricular anterior wall; LVEF, left ventricular ejection fraction; LVF, left ventricular function; LVIW, left ventricular inferior wall; LVPW, left ventricular posterior wall; LVSW, left ventricular septal wall; LVWM, left ventricular wall motion; M, mean; NCA, normal coronary angiography; NPV, negative predictive value; PPV, positive predictive value; SBP, systolic blood pressure; SD, standard deviation; SPSS, Statistical Package for the Social Sciences


According to previous studies on the deformation properties of the left atrium, the systolic strain and strain rates represent the atrial reservoir function and the early and late diastolic strain rates show the conduit and booster functions, respectively.We sought to evaluate the intra and interatrial asynchrony using strain/strain rate imaging in systolic heart failure patients.Twenty five patients with systolic heart failure (LVEF ≤ 40%) were enrolled into the study. Asynchrony quantifications were performed according to the standard deviation of time-to peak (TP-SD) of deformation of three segments manually located along the perimeter of the left atrium free wall, right atrium free wall and interatrial septum, as imaged in an apical four-chamber view. We also calculated classic echocardiography parameters such as LV end-diastolic dimension index, LA volume index, RA area, as well as deceleration time (DT) on transmitral pulsed wave Doppler and E/E’ ratio on mitral annular tissue Doppler imaging.In heart failure patients either inter or intra-atrial asynchrony were far more common in comparison with normal subjects (P=0.008 and P=0.007 respectively).Left ventricular systolic heart failure, may result in inter and intra-atrial asynchrony even in clinically stable patients without significant pulmonary hypertension and diastolic dysfunction. Structural heart disease and heart failure (HF) can lead to electrical and structural remodeling of the atria . As a reAlthough LA function can be assessed by echocardiography, using Doppler analysis of trasmitral and pulmonary vein flow and tissue Doppler assessment of myocardial velocities  yet , asIn the present study, we have used this novel tool for studying LA cavity characteristics in a group of patients with systolic heart failure. We used speckle tracking echocardiography to evaluate inter and intra-atrial asynchrony in patients with systolic heart failure.The study population consisted of 25 patients (mean age = 51 ± 13.3 years), with LV systolic dysfunction (LV EF ≤ 40%), which were referred for routine diagnostic or follow up echocardiography and twenty-four healthy adult subjects, referred for a diagnostic examination or checkup (mean age: 41.5 ± 14.5 years). All control subjects had unremarkable clinical history and normal findings on physical examination. The etiology of systolic dysfunction was either ischemic or nonischemic. The most common presenting symptom was dyspnea on exertion, functional NYHA class II – III. All subjects were in sinus rhythm and hemodynamically stable, without any significant valvular disease.Echocardiography studies were performed using Mylab 60, Esaote, S.P, A-Italy. Subjects were studied in the left lateral recumbent position. Measurement of left ventricular (LV) dimension, left atrial (LA) volume and right atrial (RA) area were made in accordance to current recommendations of the American society of echocardiography. LVEF was estimated by visual assessment and Simpson's rule. The ratio between peak early diastolic filling velocities (E) and annular early diastolic velocity (E'), late diastolic filling velocity (A), deceleration time, systolic pulmonary artery pressure and right ventricular function were determined by standard Doppler and Doppler tissue imaging. LA volume and LV end diastolic dimension were subsequently indexed to body surface area.All echocardiographic studies were performed with the subject lying in the left lateral decubitus position, obtaining complete 2D-echocardiographic color Doppler examination with a 3.5 MHz variable-frequency harmonic phased-array transducer. The LA volume was calculated according to the formula: 8/3p [/LA length] . LV globVelocity Vector Imaging (VVI) is a state-of-the-art technology that enables clinicians to examine the mechanical functions of the myocardium to determine myocardial dysfunctions and dyssynchrony -15. It uParticular attention was paid to obtain an adequate gray scale in each view and to avoid foreshortening of the left atrium, allowing a more reliable delineation of the atrial endocardial border. Three consecutive heart cycles were recorded and analyzed. Recordings were processed off line by a single experienced echocardiographer using a commercially available semi-automated two-dimensional strain software .Left and right atria endocardial surfaces were manually traced in four chamber views in end systole and the resulting tracking quality for each segment was automatically scored as either acceptable or non-acceptable with the possibility of further correction. Lastly, strain curves were generated for each atrial segment by the software .Peak R wave in ECG monitoring was the default reference point. We also considered the onset of P wave on the recorded electrocardiogram as the second reference point. Peak atrial longitudinal strain (PALS) was measured in LA segments at a distance of 0.5 - 1 cm from mitral annulus in four chambers for septal and lateral walls and 0.5- 1 cm below tricuspid annulus on right atrial (RA) free wall. First negative deflection of LA strain and strain rate curves  after P The time difference from onset of P wave to nadir of a wave at the RA free wall (P-RA), interatrial septum (P-IAS), and LA free wall (P-LA), were defined as time to atrial activation. The time difference from peak R wave to nadir of A wave at the RA free wall (R-RA), interatrial septum (R-IAS) and lateral LA wall (R-LA), were also defined  . These tTo assess the reproducibility of intra-atrial and interatrial asynchrony, five subjects were randomly selected and analyzed. Bland-Altman analysis was performed to evaluate the inter and intra-observer variability by repeating the analysis 1 week later by the same observer and a second observer and this resulted an intra-observer variability of 1.1% and an inter-observer variability of 2.2%.Data are expressed as mean ± SD for interval and count(%) for categorical variables. association between asynchrony and study groups was investigated by Student’s t test and between asynchrony and other interval variables by Pearson’s correlation coefficients. A P-value < 0.05 was considered to be significant. Statistical analysis was performed using the SPSS 16 for Windows .Baseline echocardiographic and general characteristic data are shown in There was a significant difference between time to onset of P wave and onset of atrial LA strain and strain rate curves in heart failure patients  . A signiStrain rate measures showed significant difference in intra-atrial synchrony [(P-LA)-(P-IAS): time difference between time to onset of P wave and onset of LA free wall and interatrial septum strain rate)] in heart failure patients . Inter atrial asynchrony C SR in case group was significantly different from the control group, P = 0.007. LA asynchrony SR and LA asynchrony CSR in case group was significantly different from the control group (P = 0.008 and P = 0.007 respectively), . Strain rate measures also showed significant differences in interatrial synchrony [(P-LA)-(P-RA): time difference between time to onset of P wave and onset of LA free wall and RA free wall strain rate)] in heart failure patients , .Corrected inter-atrial asynchrony and LA asynchrony by strain rate study was significantly different from control group (both P = 0.007), . There wIn this study we analyzed intra and inter-atrial asynchrony using a novel speckle tracking index in patients with advanced systolic heart failure. The results of our study suggest that 2D strain is currently available as a non-invasive tool to quantify atrial deformation and asynchrony. Since heart failure is associated with atrial conduction delay, strain contributes to a better definition of the mechanical characteristics as is known for the ventricle. In this study 2D strain using velocity vector imaging was used to evaluate intra- and inter-atrial asynchrony in patients with HF and controls. In a study by Beeumen et al.  atrial aThere are some differences between our findings and theirs. They reported a significant increase in RA asynchrony in HF patients compared with controls and patients without HF , but in our study RA asynchrony was not different between patients and control subjects . On the contrary, they were not be able to show a significant difference in LA asynchrony , although we found a significant LA asynchrony in our patients . Although in their study inter-atrial asynchrony was significantly higher , in ours it was significant just in terms of CSR .In their study, only the correlations between RA asynchrony with the ejection fraction was significant , however, we found a weak negative but significant correlation between corrected intra and inter-atrial asynchrony (strain rate imaging) and intra-atrial asynchrony (strain imaging) with LVEF . Our study showed that atrial asynchrony assessment using VVI is feasible in heart failure patients in clinical practice and some degree of either LA asynchrony and or inter-atrial asynchrony may present in patients with systolic heart failure. In addition, it is unknown that atrial asynchrony responds to cardiac resynchronization therapy.In a recent comparative study for assessment of left atrial deformation and synchrony in healthy subjects and patients with atrial fibrillation (AF) using three-dimensional speckle-tracking echocardiography Mochizuki et.al revealed that both LA longitudinal strain (LS) and circumferential strain (CS)  and also standard deviation of either left atrial systolic longitudinal strain ( LSs) or pre atrial contraction longitudinal strain (LSa) were reduced in patients with paroxysmal AF compared with controls (SD LSs (%): 9.9 ± 5.8 versus 16.1 ± 6.8, P after Bonferroni’s correction < 0.05, SD LSa (%): 20.9 ± 10.9 versus 26.4 ± 8.8), and further reduction of all parameters were observed in patients with permanent AF.18). Comparison of LA strain and synchrony between controls and patients with paroxysmal AF showed a significant dyssynchrony in patients with LA dilation (SD LSs (%): 9.9 ± 5.8 vesus 16.3 ± 7.6, P after Bonferroni’s correction < 0.05, SD LSa (%): 20.9 ± 10.9 versus 26.4 ± 8.8). In addition using two-dimensional STE, longitudinal and circumferential LA strain during ventricular systole (LSs) were significantly smaller in patients with paroxysmal AF than in controls (23.8 ± 8.6 versus 32.6 ± 6.5) (. CompariThe present study showed that VVI enables the comprehensive assessment of LA synchrony in patients with systolic heart failure with excellent reproducibility. It has been previously shown that in patients with AF, reduced LA strain determined by 2D STE is correlated with fibrosis in LA wall demonstrated by cardiac magnetic resonance imaging,  CHADS2 rAlthough, an improvement in LA atrial strain following cardiac resynchronization therapy in HF patients has been shown , further2D speckle tracking of the atria is more difficult and time consuming than those of ventricles. Both the left and right atria are farther from the transducer in the apical views, and their myocardium is thinner and brighter than the ventricular myocardium, so fewer speckles could be tracked. Another limitation was the ability to only assess longitudinal function.


However, the majority of sudden cardiac death (SCD) in patients with heart failure occurs in those with mild-moderate systolic heart failure (LVEF 36%-50%) who currently do not qualify for an ICD. At present, our tools to reliably risk stratify patients with mild-moderate heart failure to predict the likelihood of SCD are limited. Recent data however suggest that ventricular scar and/or replacement fibrosis, reliably identified on Cardiac Magnetic Resonance Imaging (CMR), forms a substrate for malignant arrhythmia, thus potentially identifying a group at increased risk of SCD. The A multi-centre randomized control trial based in Australia and Europe, enrolling 428 patients with mild to moderate left ventricular systolic dysfunction, on optimal heart failure therapy. Participants will be recruited through heart failure clinics and echocardiography databases to undergo CMR assessment for myocardial scar and fibrosis. The study will have two arms: Firstly, those with myocardial scar/fibrosis will be enrolled into a prospective, blocked, randomized control trial to receive either primary prophylaxis ICD therapy or an implantable loop recorder (ILR). Secondly, a further 521 patients without scar/fibrosis will be enrolled into an observational registry. Follow-up with be at 3, 6, 12, 24 and 36 months for the implant groups (ICD and ILR) and at 12, 24 and 36 months for the registry group.The primary endpoint will be time to sudden cardiac death, or syncopal ventricular arrhythmia during an average 3-year follow-up. The secondary endpoints consist of sudden cardiac death, syncopal ventricular arrhythmia, all-cause mortality, quality of life assessed by Minnesota Living with Heart Failure Questionnaire, heart failure related hospitalizations and a cost utility analysis.CMR as a novel tool for risk stratification by directly imaging the scar which forms a critical substrate for ventricular arrhythmia. The results of this study will result in a highly significant advance in knowledge in this field by providing new information about the potential benefits of primary prevention ICD in mild-moderate LV systolic dysfunction. If proven, it would radically alter the way in which patients are selected for ICD therapy.This study will use Biotronik Australia.NHMRC Govt of Australia.


Left ventricular (LV) mid-wall fibrosis (MWF), which occurs in about a quarter of patients with non-ischemic cardiomyopathy (NICM), is associated with high risk of pump failure. The mid LV wall is the site of circumferential myocardial fibers. We sought to determine the effect of MWF on LV myocardial mechanics.n = 116; age: 62.8 ± 13.2 years; 67 % male) underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR) and were categorized according to the presence (+) or absence (−) of MWF. Feature tracking (FT) CMR was used to assess myocardial deformation.Patients with NICM , but similar longitudinal  and radial (Ɛrr: 14.6 % vs. 17.8 % p = 0.18) strain. Compared with − MWF, + MWF was associated with reduced LV systolic, circumferential strain rate  and peak LV twist , as well as rigid LV body rotation . In addition, +MWF was associated with reduced LV diastolic strain rates .Despite a similar LVEF , patients with MWF (32 [24 %]) had lower global circumferential strain (ƐMWF is associated with reduced LV global circumferential strain, strain rate and torsion. In addition, MWF is associated with rigid LV body rotation and reduced diastolic strain rates. These systolic and diastolic disturbances may be related to the increased risk of pump failure observed in patients with NICM and MWF. Non-ischemic cardiomyopathy (NICM) is a common cause of heart failure . The NICLeft ventricular mid-wall fibrosis (MWF) was first described as an autopsy finding in 1991 . ClinicaThe left ventricle (LV) twists in systole and untwists, or recoils, in diastole. In systole, the LV base rotates clockwise and the apex rotates counter-clockwise. This wringing motion is effected by the helical arrangement of myocardial fibers, which run in a left-handed direction in the subepicardium and in a right-handed direction in the subendocardium . Contraction of subepicardial myocardial fibers cause the base to rotate clockwise and the apex to rotate in counterclockwise . BecauseWe hypothesized that injury to mid-myocardial, circumferential myocardial fibers , as mighPatients with NICM were recruited through CMR units in two centers . The initial diagnosis of cardiomyopathy was made on the basis of clinical history, echocardiographic evidence of LV systolic impairment and absence of coronary artery disease on invasive coronary angiography. The diagnosis of NICM was also made on the basis of LGE-CMR . Mid-walThis was undertaken using 1.5 Tesla Magnetom Avanto  or Signa  scanners and a phased-array cardiac coil. A horizontal long-axis image and a short-axis LV stack from the atrioventricular ring to the LV apex were acquired using a steady state in free precession (SSFP) sequence . There were 25 phases per cardiac cycle resulting in a mean temporal resolution of 40 ms.For scar imaging, horizontal and vertical long-axis as well as short-axis slices identical to the LV stack were acquired using a segmented inversion-recovery technique 10 min after the intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (0.1 mmol/kg). Inversion times were adjusted to null normal myocardium (260 to 400 ms). To exclude artefact, we required the typical scar pattern to be visible in the short-axis and long-axis acquisitions, in two different phase encoded directions. Patients were dichotomized according to the presence or absence of MWF, assessed visually by an experienced observer (F.L.), who was blinded to other study data.cc) and radial (Ɛrr) strain, strain rates (SSRcc and SSRrr) and diastolic strain rates (DSRcc and DSRrr) were assessed using FT-CMR of the mid-cavity LV short-axis cine. Longitudinal strains  were assessed using the horizontal long axis cine. Only the SSFP sequences were uploaded onto the FT-CMR software, ensuring that the operator (R.T.) was blinded to MWF status. In addition, MWF status was decided by an investigator (F.L.) who was blinded to the findings of FT-CMR.Feature tracking CMR  was undertaken as previously described. It has been validated against myocardial tagging for the assessment of myocardial mechanics , 17. We apex - Φ base), twist per unit length (Φ apex - Φ base/D), and LV torsion  as (Φ apex - Φ base)(ρ apex - ρ base) / 2D  in accordance with agreed methodologies [Peak systolic rotation was measured using the basal and apical short axis cines. In health, peak systolic rotation, as viewed from the apex, is typically clockwise (+) at the base, and anti-clockwise (−) at the apex. Peak systolic rotation was calculated in degrees and expressed as both the maximum extent of rotation in the anticipated direction  and the total magnitude of rotation (regardless of direction). Torsional parameters are derived from the peak instantaneous net difference in apical and basal rotation. LV twist was defined as .Categorical variables were expressed as a percentage and continuous variables as mean ± standard deviation (SD). Normality was tested using the Shapiro-Wilk test. Comparisons between variables were made with Fisher’s exact test for categorical variables and independent samples t-tests for continuous variables, after adjustment by the Welch-Satterthwaite method where Levene’s test showed unequal variance between groups. A p = 0.29), but more patients with MWF were men . There were no differences in NHYA class, atrial rhythm, QRS duration, LVEF, co-morbidities, pharmacological therapy for heart failure.The characteristics of the study group are shown in Table cc: −6.6 % vs −9.4 %, P = 0.004), but similar longitudinal  and radial (Ɛrr: 14.6 % vs. 17.8 % p = 0.18) strain. Systolic strain rate was reduced in the circumferential direction , but not in radial or longitudinal directions. Figure cc (r = 0.70), Ɛrr  correlated positively with LVEF. In the case of Ɛcc, the slope of the regression line was 0.17 in the + MWF group and 0.31 in the -MWF group, indicating that Ɛcc is lower in the + MWF group than in the -MWF at a given LVEF.As shown in Table cc: 0.34 vs 0.46 s−1, p = 0.01; DSRrr: −0.55 vs −0.75 s−1, p = 0.04; DSRll: 0.38 vs 0.50 s−1, p = 0.006).In patients with MWF, diastolic strains rates were lower in all three directions in patients with MWF , the rate of basal rotation was reduced . In patients with MWF, apical rotation was also reduced in terms of both the total magnitude  and the net anti-clockwise rotation . The rate of apical rotation was lower in patients with MWF . This reduction in the magnitude of apical rotation was associated with a reduction in LV twist . The rate of LV twist  and untwist  was also reduced in patients with MWF. A normal torsion pattern, in which there is predominantly anti-clockwise rotation of the apex and clockwise rotation of the base, was observed more frequently in patients without MWF (32 vs 46 %). Rigid LV body rotation was more frequently observed in patients with MWF .Whilst basal rotation was unaffected by MWF  and more likely to move as a solid body. These disturbances may be related to the known associations of MWF with reduced pump function, heart failure hospitalizations and a poor response to medical and device therapy –11.During ejection, circumferential fibers shorten simultaneously with the oblique fibers in the right- and left-handed helices to thicken the myocardium and empty the heart. We have found that MWF was associated with a selective reduction in circumferential strain, suggesting that MWF preferentially affects mid-myocardial, circumferential fibres. As noted by Buckberg , circumfWe have previously shown that patients with NICM and MWF treated with CRT are more likely to suffer pump failure than patients without MWF . On the In diastole, release of energy stored in systole (recoil) causes rapid untwisting and a mitral-to-apical negative gradient  that 'suThe LGE-CMR technique described herein only detects replacement fibrosis. The more recent technique of T1 mapping, which detects interstitial fibrosis, was not undertaken. We cannot therefore comment as to whether our findings are also influenced by the latter. In addition, we have not routinely undertaken myocardial biopsy, nor have we quantified myocardial oedema. Therefore, we cannot exclude the possibility that our findings were influenced by active myocarditis, despite the absence of evidence from clinical and laboratory screening. We should also add that different manufacturers have varying methodologies for the calculation of the mechanical variables described and therefore, our findings are not generalizable to other FT-CMR methodologies. Publication of the FT-CMR algorithms used by different manufacturers would be welcome.We have shown that in patients with NICM, MWF is associated with profound disturbances in LV global circumferential strain, strain rate, LV twist and torsion, in both systole and diastole. In addition, MWF is associated with rigid LV body rotation. These findings provide a mechanistic link between MWF and a poor clinical outcome in patients with NICM, despite pharmacologic and device therapy.


However, a gap exists in the understanding of Cl2-induced cardiac dysfunction. This study was performed to characterize cardiac dysfunction occurring after Cl2 exposure in rats at concentrations mimicking accidental human exposures (in the range of 500 or 600 ppm for 30 min). Inhalation of 500 ppm Cl2 for 30 min resulted in increased lactate in the coronary sinus of the rats suggesting an increase in anaerobic metabolism by the heart. There was also an attenuation of myocardial contractile force in an ex vivo (Langendorff technique) retrograde perfused heart preparation. After 20 h of return to room air, Cl2 exposure at 500 ppm was associated with a reduction in systolic and diastolic blood pressure as well echocardiographic/Doppler evidence of significant left ventricular systolic and diastolic dysfunction. Cl2 exposure at 600 ppm (30 min) was associated with biventricular failure (observed at 2 h after exposure) and death. Cardiac mechanical dysfunction persisted despite increasing the inspired oxygen fraction concentration in Cl2-exposed rats (500 ppm) to ameliorate hypoxia that occurs after Cl2 inhalation. Similarly ex vivo cardiac mechanical dysfunction was reproduced by sole exposure to chloramine . These results suggest an independent and distinctive role of Cl2 (and its reactants) in inducing cardiac toxicity and potentially contributing to mortality.Victims of chlorine (Cl Toxicity of Cl2 is a complex phenomenon. It consists of a primary injury to the airways and alveolar epithelia and subsequent escalation of damage by more stable secondary reactants . Cardiovascular dysfunction can also be caused and aggravated by inhalation of oxidant gases, environmentally persistent free radicals potentially derived from combustion of Cl2-containing hydrocarbons and other environmental pollutants   causing cytosolic Ca2+ overload. The objectives of this study were to (1) characterize the effects of Cl2 on cardiac function at two different levels of exposure; and (2) explore whether Cl2-induced cardiotoxicity is dependent on hypoxia. We demonstrate that inhalation of Cl2 (500 or 600 ppm for 30 min) results in severe cardiac injury (assessed by echochardiography in vivo and force of contraction measurements in isolated perfused hearts) which persists even when arterial hypoxemia (resulting from lung injury) is alleviated by the inhalation of supplemental oxygen.Exposure to 600 ppm Cl2 exposure of male Sprague–Dawley rats  was performed as described previously  was inserted into the right carotid artery and advanced to the LV. Using a Biopac MP100 system with AcqKnowledge 3.7.3 software , left ventricular end diastolic pressure (LVEDP), left ventricular peak systolic pressure (LVPSP), and the peak rate of rise of ventricular pressure at systole (dP/dt maximum) and its reduction at diastole (dP/dt minimum) were measured. Systemic blood pressure was also monitored with a Millar pressure catheter inserted in the femoral artery.E) and atrial (A) wave peak velocities, isovolumic relaxation time (IVRT), E-wave deceleration time, and isovolumic contraction time, with the ratio of E to A calculated. Peak early (E′), atrial (A′), and systolic (s=) annular velocities were recorded, and (E) to (E′) ratios were calculated. LV fractional shortening (LVFS), LV ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and end diastolic volume (LVESD), and end-systolic and end diastolic dimensions were measured for the assessment of LV systolic function. The 2D echocardiographic images acquired from the parasternal long-axis and short-axis views were analyzed using 2D speckle-tracking software . Each image of the LV myocardium was divided into six standard anatomic segments throughout the cardiac cycle. Longitudinal and transverse strains were assessed from long-axis views, whereas radial and circumferential strains were assessed from short-axis views. A (−) sign was given for a decrease in dimension and a (+) sign was given for an increase in dimension. We measured peak systolic global strain. All strain data were measured over three heartbeats and averaged. Two observers with expertise in echocardiography assessed the studies for intra- and interobserver reproducibility of longitudinal, transverse circumferential, and radial tracking.Cardiac images were acquired in anesthetized animals (ketamine 80 mg/kg) using a Vevo2100 high-resolution ultrasound system  with a 13-MHz to 24-MHz linear transducer (MS-250). Rats were placed supine on the warmed stage of the echocardiography system. Parasternal long- and short-axis two-chamber M-mode and B-mode views were obtained at mid papillary level and averaged to determine LV dimensions at end-systole and end-diastole. LV volumes, cardiac output, fractional shortening, and ejection fraction were obtained. Apical 4-chamber B- and M-modes were obtained to determine tricuspid annular plane systolic excursion (TAPSE), transmitral flow and septal mitral annular tissue displacement. Spectral Doppler was used to determine transmitral early  for multiple comparisons. All echocardiography analysis and calculations were performed using SPSS version 19.0 .Means were compared by two-tailed 2 (30 min) and returned to room air for up to 20 h. There was an increase in arterial blood (AB) and coronary sinus (CS) lactate of Cl2-inhaling rats (1.38 ± 0.05 mg/dL at 0 ppm vs. 5.33 ± 1.93 mg/dL at 500 ppm in AB when measured at 3 h after Cl2 exposure). Coronary sinus (CS) lactate levels were elevated in rats exposed to Cl2 (500 ppm) that were then returned to room air for 20 h   and decreased oxygen saturations (96 ± 1% at 0 ppm vs. 86 ± 2% at 500 ppm) when rats were exposed to 500 ppm Cl20 h Fig. and B. Ippm) Fig..2 were explored by surface echocardiography. Echocardiography was performed at 20 h after Cl2 inhalation under ketamine anesthesia. The results showed a significant decrease in left ventricular end-systolic diameter (LVESD) and volume (LVESV). LVEDV was unchanged, resulting in a significant increase in LV ejection fraction (LVEF)  to late (A) peak diastolic velocities across the mitral valve (E/A) and a significant reduction in early diastolic mitral annular tissue velocity (E′) as well as a significant increase in the ratio of early diastolic transmitral peak velocity to early mitral annular tissue velocity (E/E′)  Fig. and B in/E′) Fig. and D.2 vs. 7270 ± 62, P = 0.027) at 0 ppm Cl2) and (dP/dt minimum)  . The heart/body weight ratio of Cl2-exposed animals was significantly increased (0.003667 ± 0.00006 for 0 ppm vs. 0.0044 ± 0.00005 for 500 ppm at 20 h postexposure duration), reflecting an increase in extravascular cardiac fluid.There was a reduction in both (dP/dt maximum) (4425 ± 542 at 500 ppm ClCl2) Fig.. A direc2 for a 30 min period encountered during the Graniteville train derailment were 6868, 837, and 59 ppm at 0.2, 0.5, and 1 km downwind from the epicenter of the accident  an increase in LVESV toward those of controls  of chloramine caused a gradual decline in the cardiac force of contraction and beats. Further lower concentration of chloramine (10 μmol/L) though not significantly altering the force of contraction, was associated with a reduction in the frequency of beats during the observed 30 min duration.We also measured ex vivo heart function with retrograde perfusion with Cl min Fig.. Interes2 inhalation causes severe injury to the lungs along with pulmonary and systemic vasculature  inhalation in rats  in the plasma of Cl2-exposed rats  after its cytosolic release. Mishandling of Ca2+ due to SERCA dysfunction causes Ca2+ overload and serious cardiac injury in the form of cardiac remodeling, cardiac dilatation and failure  was observed in cardiomyocytes isolated from hearts of Cl2-inhaling rats and more recently in human airway smooth muscle cells exposed to Cl2  retrograde perfused heart preparation. A reduction in systolic and diastolic blood pressure as well as a significant left ventricular systolic and diastolic dysfunction was observed. Higher concentration Cl2 exposure (600 ppm) was associated with biventricular failure and death. Cardiac mechanical dysfunction persisted despite increasing the inspired oxygen fraction concentration in Cl2-exposed rats to ameliorate hypoxia that occurs after Cl2 inhalation. Similarly ex vivo cardiac mechanical dysfunction was reproduced by exposure to chloramine .Cl+-K+ ATPase activity may also cause increased lactate production in the absence of anaerobic conditions  is associated with severe cardiac chamber dilatation and lethal myocardial depression. On the other hand, Cl2 exposure at 500 ppm resulted in a hyperdynamic LVEF in vivo despite intrinsic myocardial depression ex vivo. We posit that the unloading effect of a decrease in BP together with an expected increase in adrenergic drive over-rides the decrease in cardiac SERCA activity . Howeve