Two-dimensional strain measurements obtained by speckle tracking echocardiography (STE) have been reported in both humans and dogs. Incorporation of this technique into canine clinical practice requires the availability of measurements from clinically normal dogs, ideally of the same breed, taken under normal clinical conditions.The aims of this prospective study were to assess if it is possible to obtain STE data during a routine echocardiographic examination in Irish Wolfhound dogs and that these data will provide reference values and an estimation of measurement error.Fifty- four healthy mature Irish Wolfhounds were used. These were scanned under normal clinical conditions to obtain in one session both standard echocardiographic parameters and STE data. Measurement error was determined separately in 5 healthy mature Irish Wolfhounds.Eight dogs were rejected by the software algorithm for reasons of image quality, resulting in a total of 46 dogs (85.2%) being included in the statistical analysis. In 46 dogs it was possible to obtain STE data from three scanning planes, as well as to measure the rotation of the left ventricle at two levels and thus calculate the torsion of the heart. The mean peak radial strain at the cardiac apex (RS-apex) was 45.1 ± 10.4% (n = 44), and the mean peak radial strain at the base (RS-base) was 36.9 ± 14.7% (n = 46). The mean peak circumferential strain at the apex (CS-apex) was -24.8 ± 6.2% (n = 44), and the mean peak circumferential strain at the heart base (CS-base) was -15.9 ± 3.2% (n = 44). The mean peak longitudinal strain (LS) was -16.2 ± 3.0% (n = 46). The calculated mean peak torsion of the heart was 11.6 ± 5.1 degrees (n = 45).The measurement error was 24.8%, 26.4%, 11.5%, 6.7%, 9.0% and 10 degrees, for RS-apex, RS-base, CS-apex, CS-base, LS and torsion, respectively.It is concluded that this technique can be included in a normal echocardiographic examination in large breed dogs under clinical conditions. The usefulness of the reference values reported here, given their wide normal range, will ultimately be determined by the values that are obtained from a large numbers of diseased dogs. The Gold standard for describing myocardial movement in three dimensions has, until recently, been MRI tagging in humans and sonomicrometry in dogs . Both meCurrently, other methods are available. These methods have been validated against MRI tagging and sonomicrometry and have been found to be acceptable . One sucSTE can measure “regional strains”, which are dimensionless measurements of deformation that are expressed as a fractional or percentage change from an object’s original dimension:l is the instantaneous length, l0 is the initial length, and Δl is the change in length.where Three scanning planes are identified for strain measurements. They result in radial, circumferential and longitudinal measurements referring to changes in ventricle wall thickness, ventricular circumference and the apex-to-base dimension, respectively.During systole, radial strain (RS) is expected to be a positive value, Figures , 2 and 3STE mapping of cardiac movement over a period has been validated in humans for the assessment of various heart diseases, including ischaemic lesions and dilated cardiomyopathy (DCM) ,6. The tThe normal reference ranges for a breed that has a high prevalence DCM, a cardiac disease relevant to the technique, obtained under normal clinical imaging conditions will help determine if STE measurements can be used to meet these diagnostic and prognostic gaps.The aims of this study were to obtain LV systolic strain and torsion data using STE in a clinical setting, from healthy, mature Irish Wolfhound dogs, to report reference intervals and to estimate the measurement error.All of the dogs presented for inclusion (n = 54) were participants in a dilated cardiomyopathy (DCM) screening program in Denmark and Norway, where breeders are recommended to submit their dogs for an annual ECG and echocardiographic examination. The dogs were accustomed to echocardiographic examination. Dogs younger than one year old were excluded. All were healthy and free of medication and had no history of heart or respiratory disease. Informed owner’s consent for each dog was obtained before inclusion. A clinical examination, ECG, in right lateral recumbency according to normal procedures , and a sSTE echocardiographic images were obtained with the dogs positioned primarily in right lateral recumbency, using right parasternal short-axis views at the level of the apex and at the base of the LV, and left parasternal apical four-chamber views. The left parasternal apical four-chamber view was obtained with the dogs positioned in left lateral recumbency if the image from the right lateral recumbent view was considered inadequate. All of the dogs were imaged without sedation. One complete image set per dog, consisting of at least three consecutive cardiac cycles, was stored for later analysis.a or a Vivid E9 BT 11 M5S transducer.a The post-processing calculation of the LV strain and torsion was performed using software available as an option in EchoPac 110.1.2.b “Manual marking” of the myocardium was performed as described in previous studies , and the mean weight was 66.09 ± 9.17 kg [range: 53-85], both parameters were normally distributed.The total extra time used per dog to obtain the 3 views for STE was approximately 2 minutes. The post-processing calculation time was approximately 5 min. per dog.There was a total of six outliers, two for the radial measurements, two for the circumference measurements at the apex level, and one each for the circumferential strain measurements at the base and for the twist measurements. The outliers were removed before the reference intervals were calculated. A box and whisker plot for each parameter (with outliers removed) is shown in Figures The null hypothesis in the Shapiro-Wilk test, i.e., that the samples come from a normal distribution, was not rejected for any of the parameters. The 95% reference interval was calculated as the mean ± 2SD. This interval, the mean of the data and the number of samples for each parameter are provided in Table Measurement errors, expressed as coefficient of variation and the repeatability statistic, are provided in Table The determination of reference values is a complex procedure. Veterinary studies are often limited by small population sizes, due especially, in clinical settings, to economic and availability considerations. The American Society of Veterinary Clinical Pathology (ASVCP) addressed these issues in recently published guidelines for the determination of reference intervals in veterinary species . We usedThe criterion that all 18 segments in our STE exam yield strain measurements was also adopted in this study to provide reliable data. This strict inclusion criterion resulted in the exclusion of eight out of 54 dogs (14.8%). In a previous study using STE to measure left ventricle radial strain in dogs, 5% of the segments showed poor tracking . In humaThe values obtained in this study relate to one breed. Mean peak LV systolic radial strain values have been published in 37 healthy dogs from 20 different breeds . The LV Longitudinal strain in our study was -15.9 ± SD 3.2%. Only the left parasternal apical four-chamber view, with a total of six segments, was used in our study. According to the guidelines of the American Society of Echocardiography , three aTorsion in our population was reported as 11.6 ± SD 5.1 degrees. This result is higher than that reported (8.4 ± 3.8 degrees) in a study of 35 healthy dogs of different breeds . If the The magnitudes of the ranges for all STE strain measurements and for torsion were larger compared to those of a previously published study . The repThe usefulness of the reference values reported here, given their wide normal range, will ultimately be determined by the values that are obtained from diseased dogs. A wide range of normal values is not of any concern if a large proportion of abnormal dogs have values that fall outside this range. We are aware that our population could include dogs with occult DCM not detectable clinically or on routine echocardiographic examination. Occult DCM is of course a concern of great importance when our aim is to provide reference values for a healthy population of mature Irish Wolfhounds. It has been shown in a Great Dane with no clinical findings but equivocal findings of DCM obtained by conventional 2-dimensional and M-mode echocardiography where few ventricular premature complexes also where noted during the examination  that TisEven though the STE has been shown to be both repeatable and reproducible for assessing systolic LV torsional deformation having within day and between day variability’s less than 10% for radial strain measurements ,12, inteIn humans, the availability of reference values for STE in healthy populations has made it possible to quantify the severity of heart disease. It has been shown that apical rotation is a quantitative marker in patients with dilated cardiomyopathy. Using the STE technique, targets can be set for preventive strategies that might reduce the prevalence of heart failure in this group of patients ,23,24.STE is still a novel, but very promising, technique. The measurements are not very time-consuming to obtain, but they are nonetheless demanding to acquire in that high-quality images, high-end equipment and dedicated proprietary software, such as EchoPac, are required.Despite these considerations, it is likely that the technique will become more widely available and will be the subject of further investigation in veterinary echocardiology. STE has shown promise in several pathological human conditions, and it remains to be seen whether this promise will also be seen in veterinary medicine.Some limitations of this study can be identified. The filtering algorithms used by software in tracking the speckles from the myocardium can vary from vendor to vendor. It is thus unclear how the values from different scanners and software versions would compare. Cross-platform comparisons and a clear definition of global and regional normal values are essential for broader application of STE .The measurement of LV longitudinal strain was obtained from the left parasternal apical four-chamber view with the dog positioned in right lateral recumbency. Obtaining such images (in dogs with a mean body weight of 66 kg) was demanding on both the equipment and the sonographer. In approximately one out of 5 cases, the dog was moved from right to left lateral recumbency to improve image quality for this view. This manoeuvre could have introduced a source of measurement error. However, it should be noted that the reference range is not unusually wide for this parameter.From this study, it can be concluded that it is possible to obtain STE measurements, including radial, circumferential, and longitudinal strain and the twist of the left ventricle, in large-breed dogs under clinical conditions. The normal reference values provided here for Irish Wolfhound dogs, a breed with a genetic disposition for cardiac disease, could be useful in guiding the interpretation of STE measurements in clinical practice.aGE Healthcare, Copenhagen, Denmark.bEchoPac PC 110.1.2 software for Vivid 7 and Vivid E9 GE Healthcare, Copenhagen, Denmark.cR version 2.14.1 (2011-12-22) 2011 The R Foundation for Statistical Computing ISBN 3-900051-07-0.AO: Aorta; BSA: Body surface area; CS: Circumferential strain; DCM: Dilated cardiomyopathy; ECG: Electro cardiography; EPSS: E-point to septal separation; FS: Fractional shortening; LA: Left atrium; LS: Longitudinal strain; LV: Left ventricle; RS: Radial strain; SD: Standard deviation; STE: Speckle tracking echocardiography; TDI: Tissue doppler imaging.Both authors declare that they have no competing interests.UW headed the study, performed the echocardiographic examination and the data processing on the Echopack and was main responsible for drafting the manuscript. FJM contributed with substantial statistic work as well as participating in the design and writing the manuscript. Both authors read and approved the final manuscript.


Myocardial perfusion and strain  are reduced in severe aortic stenosis (AS). It is thought that reduced perfusion occurs in the subendocardium secondary to increased LV pressure, leading to fibrosis and reduced LS. This relationship between perfusion, diffuse fibrosis and multidirectional myocardial strain has not been previously investigated in moderate (or severe) AS.We hypothesized that impaired myocardial perfusion occurs in patients with moderate AS, leading to a degree of diffuse fibrosis  and impaired longitudinal strain.32 patients with moderate AS (by echo criteria) and 12 age and sex-matched normal controls were recruited. All subjects underwent CMR scanning at 1.5T including valve assessment, stress and rest perfusion, tagging, and non-contrast T1-mapping using the ShMOLLI (Shortened Modified Look-Locker Inversion recovery) sequence, which was previously shown to have a good correlation with histological quantification of diffuse fibrosis. Myocardial perfusion reserve index (MPRI) and strain values were derived from analysis of the perfusion and tagging sequences respectively.Despite being well matched for age and sex, there were significant differences between patients with moderate AS and normal controls in longitudinal strain, MPRI and LV mass p<0.0001, Table , Table 1In moderate AS, there is a moderate correlation between reduced MPRI and impaired longitudinal strain but not circumferential strain. This supports the hypothesis that impairment of myocardial perfusion in AS predominantly affects the subendocardial longitudinal myocardial fibers .The exact relationship of perfusion and diffuse fibrosis in moderate AS remains to be fully established however. Non-contrast T1 values (as a surrogate marker for diffuse fibrosis) were not affected by changes in myocardial perfusion but were affected by LV mass in AS patients.This study is funded by the British Heart Foundation, Heart Research UK and the National Institute for Health Oxford Biomedical Research Centre.


The aim of this study was to verify the benefits and limitations of repeated bedside echocardiographic examinations in children during mechanical ventilation. For the purposes of this study, we selected the data of over a time period from 2006 to 2010.A total of 235 children, average age 3.21 (SD 1.32) years were included into the study and divided into etiopathogenic groups. High-risk groups comprised: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS), return of spontaneous circulation after cardiopulmonary resuscitation (ROSC), bronchopulmonary dysplasia (BPD), cardiomyopathy (CMP) and cardiopulmonary disease (CPD). Transthoracic echocardiography was carried out during mechanical ventilation. The following data were collated for statistical evaluation: right and left ventricle myocardial performance indices , left ventricle shortening fraction (SF), cardiac output (CO), and the mitral valve ratio of peak velocity of early wave (E) to the peak velocity of active wave (A) as E/A ratio. The data was processed after a period of recovery, i.e. one hour after the introduction of invasive lines (time-1) and after 72 hours of comprehensive treatment (time-2). The overall development of parameters over time was compared within groups and between groups using the distribution-free Wilcoxons and two-way ANOVA tests.A total of 870 echocardiographic examinations were performed. At time-1 higher average values of RV MPI  were found in all groups compared with reference values. Left ventricular load in the high-risk groups was expressed by a higher LV MPI  and lower E/A ratio , SF  and CO . At time-2 RV MPI were lower , but remained higher compared with reference values . Other parameters in high-risk groups were improved, but remained insignificantly different compared with reference values.Echocardiography complements standard monitoring of valuable information regarding cardiac load in real time. Chest excursion during mechanical ventilation does not reduce the quality of the acquired data. The severity of a patient's clinical condition is proportional to the quality of blood circulation, changes in cardiac loading conditions, and global myocardial performance. Relevant and easily interpretable information regarding the current hemodynamics is essential for effective and safe therapeutic manipulation of blood circulation. The issue of non-invasive hemodynamic monitoring of critically ill patients using echocardiography has been extensively studied -4. The WAt our centre we prefer minimally invasive techniques to collect clinically useful hemodynamic data. Since 1997, we utilize bedside echocardiography as an integral component of established comprehensive care of critically ill children.Echocardiographic views and measurements were carried out as recommended by ASE/EAE . For theWe aimed to verify the benefits and limitations of repeated bedside echocardiographic examinations in children during mechanical ventilation.All patients included in the study were subjected to full history taking, physical examination, routine investigations, twelve lead ECG and chest X-ray. All children were monitored for vital functions, i.e. heart and respiratory rate, pulse oxymetry, ECG and one-hour diuresis. Systemic arterial and venous pressures were invasively measured with vascular catheters. The first bedside echocardiographic evaluations of cardiac performance were performed on patient admission to the PICU, and then repeated according to clinical urgency. Symptoms of severe circulatory compromise and reduction in systemic pressures were indications for further detailed investigations. In such cases, patients were examined using detailed echocardiographic techniques in a specialized laboratory using a GE Vivid 7 ultrasound apparatus . Hemodynamics were monitored simultaneously using other minimally invasive techniques such as Vigileo  or Uscom .Protective conventional mechanical lung ventilation was conducted based on the principle of positive pressure ventilation . Non-conAccording to the prevailing etiopathogenesis of respiratory failure, patients were divided into eight groups and all data was evaluated in these groups. Etiopathogenetic groups comprised of acute lung injury patients and those with acute respiratory distress syndrome (ALI/ARDS), asthmatic condition, bronchiolitis acuta (BOA), return of spontaneous circulation after cardiopulmonary resuscitation (ROSC), bronchopulmonary dysplasia (BPD), cardiomyopathy (CMP), cardiopulmonary disease (CPD), severe sepsis and septic shock according to the Society of Critical Care Medicine (Sepsis).Data was assessed at two separate intervals: after a period of recovery, i.e. one hour after the introduction of invasive lines (time-1) and after 72 hours of comprehensive treatment (time-2).For evaluation of cardiac load and myocardial performance during mechanical ventilation, we chose the following echocardiographic parameters: Right ventricle myocardial performance index (RV MPI), left ventricle myocardial index (LV MPI), left ventricle shortening fraction (SF), cardiac output  and mitral valve ratio of the peak velocity of early wave  to the peak velocity of active wave  to quantitative evaluation of the left ventricle mechanics (E/A ratio).Patients during mechanical ventilation were investigated at their bedside using transthoracic echocardiography (TTE). The TTE examination was performed using commercially available MicroMaxx  with high-resolution 3.5-5.5 MHz sequential transducer equipment and calculation package. M-mode, two dimmensional (2D), spectral flow and color Doppler imaging were performed according to the consensus recommendations of professional societies .M-mode and 2D examinations were performed in standard axis modes . The lefLeft and right ventricular ejection time was measured in the ascending aorta or pulmonary trunk just above the corresponding valve. Myocardial performance index (MPI) was then calculated using MPI = (AVCO - ET) / ET selectively for the right (RV MPI) and left (LV MPI) heart ventricles ,11. The The average value of these three indices was stored in a database. This data was used for statistical processing.P< 0.05 was accepted. All the data were analyzed using statistical software .All measured parameters were presented as a mean with standard deviation (mean ± SD). For qualitative analysis and a comparison of the distribution of studied parameters of groups, a Student's t-test and distribution-free Wilcoxons test applied. The overall development of studied parameters over time was compared between both groups using the two-way ANOVA test. A level of statistical significance of The study included a total of 235 children. Their clinical characteristics on admission are presented in Table A total of 870 echocardiographic examinations were performed during the study. In addition, we also performed an additional 60 echocardiography examinations in 60 hemodynamically stable children, in order to obtain reference values of the parameters: RV MPI 0.21 ± 0.01), LV MPI (0.29 ± 0.02), SF (0.47 ± 0.02), CO (2.94 ± 1.03) and E/A ratio (1.36 ± 0.64). Reference data values of the MPIs were in agreement with the reference values of British authors [1 ± 0.01,We assume that the update MPIs of our calculations by parallel R-R interval of ECG was the cause of our lower reference data  compared with MPI data of other studies .Distribution of patients in the etiopathogenetic groups, their basic characteristics, presence of structural heart defects, functional cardiac abnormalities and the ratio of actual to predicted mortality in the groups are listed in Table The most affected patients were in groups ALI/ARDS, BPD, ROSC, CMP, and CPD. These populations can be described as high-risk groups with highest real mortality (RAMP ratio). Not surprisingly, the CPD group was identified as having the highest number of structural congenital heart defects with significant left-right shunt, such as ventricular septal defects, atrioventricular septal defects, patent arterial duct or common arterial trunk. The average value of the PPG tricuspid valve regurgitation was 23.63 ± 2.55 torr and mitral regurgitation 10.42 ± 1.67 torr.An overview of data obtained at time-1 is presented in Table Data obtained at time-1 in the high-risk groups was expressed for greater clarity as a percentage of reference values in Figure At the beginning of the study, i.e. at time-1 of the study, the RV MPI  were higher in all etiological groups of critically ill children compared with reference values. In the high-risk groups there were also higher LV MPI  and lower SF , CO  and E/A ratio , compared with reference values. Within the high-risk groups SF , CO  and E/A ratio  were lowest in the ROSC group. The findings correspond to the etiopathogenesis and clinical severity of this group.Differences in data over time in each group were interesting. The differences within groups at time-2 and time-1 are presented in Table The data obtained at time-2 in the high-risk groups was also graphically expressed as a percentage of reference values and presented in Figure The values of all monitored parameters had a positive trend in chronological order. After three days of intensive care, i.e. at time-2 of study, average RV MPI remained higher  in all etiological groups compared with reference values. In the high-risk groups also remained higher average LV MPI  and lower average CO , compared with reference values. At time-2 there were the smallest differences in the CMP group. In this group the E/A ratio , SF  and the values of CO  remained the lowest. The results suggested a low compliance and low left ventricular contractility in the CMP group compared with the results of other groups at time-2. In the ROSC group at time-2, values of LV MPI, SF, CO, and E/A ratio were found to be improved, but RV MPI  remained the highest compared with the high-risk groups. The result corresponded to increased right ventricular afterload in this group.Quantitative evaluation of data changes over time was informative. The difference between complete dataset obtained at time-2 and time-1 using the Wilcoxon paired test are presented in Table The benefits of MPIs have been widely discussed in the literature. MPI values provide comprehensive information regarding systolic and diastolic ventricular function in real time -15.The study demonstrated that a combination of respiratory failure and mechanical ventilation significantly increased the right ventricular loading conditions, regardless of the etiology of the disease. Since the beginning of our study, we evaluated the global performance of the right ventricle using RV MPI due to it being technically simpler. The variability of the RV MPI data set was 0.00316, sensitivity of RV MPI was 0.891, and specificity 0.814. To assess right ventricular systolic function it could be more useful to measure the tricuspid plane systolic annular excursion (TAPSE) [On the contrary, LV MPI and CO varied according to the etiopathogenesis of disease in the other groups. The variability of the LV MPI data set was 0.00501, sensitivity of LV MPIs was 0.878, specificity 0.834. Normalization values of the monitored parameters and rate of change was dependent on the etiopathogenesis of the disease. Our results support the conclusions of other studies that determined a high degree of confidence between MPIs and cardiac loading conditions. Nevertheless the MPIs being dependent on loading conditions closely follow changes in myocardial function and appear to have predictive value mainly in myocardial dysfunction ,18. ThisThe authors are aware that echocardiography during mechanical ventilation has limitations related to methodology, parameter selection and investigator experience. Relative methodological limits of echocardiographic views are ventral pneumothorax, or left-sided alveolar hyperinflation. The presence of a larger volume of air between the ultrasound probe and the heart, lodged deep in the chest reduces image quality. A cardiologist using M-mode may reveal a ventral pneumothorax and is thus forced to seek non-standard projections for further examination of the heart. Modern ultrasound procedures enable high quality assessment of lung parenchyma under the B-line . In suchRepeated bedside echocardiography is a useful addition to the comprehensive hemodynamic monitoring of critically ill children. The absolute values of the measured parameters are not as important as the dynamic changes during the course of treatment.Breathing chest excursion during mechanical ventilation does not diminish the quality of echocardiography. Echocardiography complements monitoring of valuable information regarding the morphology and real-time changes in ventricular loading conditions. Repeated bedside examination enables the control of functional changes, current compliance and overall biventricular performance. Tracking changes in cardiac performance contributes towards the effectivity of treatment. Cardiac output and hemodynamics are affected by the etiology of the disease, management strategies and treatment time.ALI/ARDS: acute lung injury and acute respiratory distress syndrome; Asthma: asthmatic condition; AVCO: time interval from cessation to the onset of mitral or tricuspid inflow; BOA: bronchiolitis acuta; BPD: bronchopulmonary dysplasia; CO: cardiac output (according to the Teichholtz formula); CMP: cardiomyopathy; CPD: cardiopulmonary disease; E/A ratio: mitral valve ratio of peak velocity of the wave E to wave A.; LV MPI: left ventricle myocardial performance index; PRISM: Predicted Risk of Mortality Score (pediatric version); PICU: Paediatric Intensive Care Unit; PPG: peak pressure grading; RAPM ratio: Ratio of Actual to Predicted Mortality; ROSC: return of spontaneous circulation after successful cardiopulmonary resuscitation; RV MPI: right ventricle myocardial performance index; Sepsis: severe sepsis and septic shock ; SF: left ventricle shortening fraction; TTE: transthoracic echocardiography.The authors declare that they have no competing interests.JK and ZS introduced the study idea. JK, JF and PJ acquired the echocardiography images, KP and LS helped in the interpretation of the results, and SF helped with data collection. JK wrote the manuscript, ZS and KP added clinical discussion to the manuscript. ZS reviewed the manuscript. Finally, all authors read and approved the manuscript.


This prospective study is designed to identify novel imaging (utilizing cardiovascular magnetic resonance and advance echocardiography) and biochemical markers to detect early, sub-clinical cardiotoxicity following chemotherapy.Cardiac toxicity is an important long term side effect of anthracyline chemotherapy. We hypothesized that novel cardiovascular magnetic resonance (CMR) and echocardiographic markers of myocardial function, oedema, and necrosis can detect early, subclinical cardiac toxicity in patients receiving anthracycline therapy for breast cancer.29 chemonaive patients with breast cancer (early stage and metastatic), underwent serial cardiovascular magnetic resonance imaging , advanced echocardiography (for LV strain in addition to standard measurements of LV diastolic function), pro brain natriuretic peptide (pro-BNP) and high-sensitivity Troponin T  measurements. All tests were conducted at baseline, 1 month, and 3 months following commencement of anthracyclines. 6 normal volunteers  underwent the same CMR protocol. For oedema imaging, a triple inversion recovery fast-spin echo sequence (short-TI inversion recovery) was used in 3 short-axis views of the left ventricle. For assessment of myocardial oedema, the ratio of mean signal intensity (SI) of the myocardium was compared to that of skeletal muscle.In the study patients, the mean CMR LV end-systolic volume index (LVESVI) increased from baseline of 17.8 ± 6.2 to 20.3 ± 5.9 mL/m2 (p<0.001) at 1 month and remained significantly elevated at 3 months . Similarly, the end-diastolic volume index (LVEDVI) increased from 62.9 ± 11.6 mL/m2 at 1 month to 66.4 ± 11.8(p<0.000) at 3 months . Echocardiographic measurement of global longitudinal strain (GLS) showed no significant change at 1 month, however decreased in absolute magnitude from -21.4 ± 3% baseline to -19.5 ± 1% (p ≤ 0.001) at 3 months. Left ventricular diastolic function did not change significantly in study patients, either 1 or 3 month post chemotherapy. BNP did not correlate significantly with observed changes in LVEDV, LVESV and GLS. Hs-TnT did not change at 1 month but increased from 3.8 ± 1.6 to 10.7 ± 9.8 at 3 months (p ≤ 0.003). Although there was no difference between baseline values of T2 ratio between normal volunteers and study patients, 15/26 (58%) of patients had an abnormal T2 signal (SI increase to > 1.9 as specified by Lake Louis criteria) in one or more short axis slices post chemotherapy. There was no new late gadolinium hyperenhancement to suggest focal myocardial necrosis/fibrosis in any patient following therapy.Our data suggest that there are subtle functional changes in the LV myocardium early post anthracycline chemotherapy that can be detected by both CMR and advanced echocardiographic techniques. This is likely mediated by myocardial inflammation (without necrosis). These findings may be a basis for development of early predictors of cardiac damage and earlier intervention/preventative strategies.This study has received a grant from FMC Foundation, Adelaide, Australia.


Background. In this study, we evaluated the association between diastolic dysfunction severity and severity of cirrhosis in nonalcoholic cirrhotic patients. Methods. This cross-sectional study was conducted on all nonalcoholic cirrhotic patients who were admitted in Rasht Razi hospital the Cancer of Guilan Province, north of Iran, from January 2011 to March 2012. Severity of cirrhosis was evaluated by Child-Pugh score. A 12-lead surface ECG and echocardiographic studies were performed. We used a HDI 3000  equipped with 2 to 4 MHz probes. Diastolic function was determined by an expert cardiac sonographer. Data were analyzed by SPSS for win (version16). A P value less than 0.05 was considered significant. Results. Sixty-tree percent of patients were male. The mean age of patients was 52.78 ± 15.2 years. 22%, 38%, and 40% of patients were considered as child class A, B, and C, respectively. There was a significant relation between diastolic dysfunction and disease duration (P = 0.001), female gender (P = 0.004), age > 60 years (P = 0.045), and severity of cirrhosis (P = 0.048). On multivariate analysis, decreased E/A ratio (P = 0.03) and disease duration (P = 0.02) showed an independent significant relation. Conclusion. According to the relation between severity of cirrhosis and diastolic dysfunction, we recommend cardiac assessment in all child B and C cirrhotic patients. Cirrhosis is a hepatic disease that presents in individuals aged 50–60 years, typically , 2. PatiCirrhotic cardiomyopathy is the term used to describe a collection of characters expressive of abnormal heart structure and function in patients with cirrhosis , 8. The Many patients with cirrhosis exhibit various degrees of diastolic dysfunction. Diastolic relaxation is damaged in cirrhosis. Diastolic filling consists of two parts normally: rapid, early diastolic (active) relaxation and late diastolic (passive) filling. The first phase depends on the rate of ventricular relaxation, elastic ventricular recoil, the atrio-ventricular pressure gradient, and the passive elastic features of the left atrium and ventricle , 13.The second phase formed on the basis of the strength of left atrial contraction and the stiffness of the left ventricle. Diastolic dysfunction occurs when the passive elastic traits of the myocardium are reduced to increased myocardial mass and changes in the extracellular collagen secondarily . This leVentricular diastolic compliance and diastolic function can be assessed by measuring the velocity of blood flow from the left atrium to the left ventricle during early diastole (the E wave) and late diastole (the A wave) and calculating the E/A ratio by using the Doppler echocardiography . In otheMany studies indicated that some level of diastolic dysfunction exists in most patients with cirrhosis –23. DiasThis survey was conducted as a cross-sectional descriptive study. All nonalcoholic cirrhotic patients who were admitted from January 2011 to March 2012 were enrolled.Severity of the cirrhosis was evaluated by Child-Pugh criteria and divided in three groups: A (mild), B (moderate), and C (severe).This study project was approved by the ethics committee of the faculty of medicine, Guilan University of medical sciences, Iran. A written informed consent was obtained from each patient.A 12-lead surface EGG was obtained from all subjects in the supine position immediately before echocardiography by using machine. The ECG was recorded at a paper speed of 50 mm/s. All measurements were made by one observer who was not aware of the patients' characteristics.Echocardiographic studies were performed using a HDI 3000  equipped with 2 to 4 MHz probes allowing M-mode, two-dimensional, and pulsed Doppler measurements. An experienced cardiac sonographer performed the measurements. Echocardiography was performed according to the guidelines of American Society of Echocardiography .The diastolic function was evaluated by the following indexes: left ventricular filling derived from mitral valve diastolic flow velocity curve, such as the ratio of E and A wave velocities (E/A); the atrial deceleration time (DT); and Early filling wave (Ea). The E wave corresponds to the peak initial mitral inflow velocity and the A wave to the velocity caused by atrial contraction. DT is associated with the left ventricular relaxation and corresponds to the slope of a straight line from the peak to half of the E velocity. The normal value is greater than or equal to 1.0 for the E : A ratio, less than or equal to 240 msec for ADT, and less than or equal to 110 msec for IRT. Diastolic dysfunction was present if one or two of the above parameters were present .P value <0.05 was considered significant.SPSS for Windows, version 16, was used for data analysis. The qualitative data were analyzed by chi-square and Fisher's exact test. Continuous variables are presented as mean ± standard deviation (SD); categorical variables are presented as percentages. We also use the multivariate analysis to reject confounders. P = 0.001).P = 0.004) and it was more frequent in female patients . The age group of >60 years was the most frequent group of diastolic dysfunction. Up to 73.3% of cirrhotic patients in this group had some degree of diastolic dysfunction (There was a significant relation between diastolic dysfunction and age (function .P = 0.048) (P = 0.03) and disease duration (P = 0.02) showed an independent significant relation.The relation between severity of cirrhosis and diastolic dysfunction was significant in this study (= 0.048) . On multP = 0.001).Half of advanced cirrhotic patients had cardiac dysfunction. Diastolic dysfunction is a complex process that arises from numerous interrelated contributing factors such as pressure variations in the ventricle, cardiac preload and afterload, and ventricular relaxation and compliance . The incP = 0.004). Similarly, in the study of Redfield et al. they showed that heart failure with normal ejection fraction in any ages is more frequent in women rather than men [In this study, diastolic dysfunction in women was significantly more than men . It was also seen in the study of Nasr et al. [In our study, diastolic dysfunction was increased significantly by increasing duration of disease . The same results can be seen in other studies like El-Adi et al. that concluded cardiac changes is age related in cirrhotic patients in comparison with control group and showed that incidence of diastolic dysfunction was increased by age [Correlation of age and diastolic dysfunction is important for managing and predicting the prognosis of disease. In our study, age group of >60 years had more diastolic dysfunction (d by age . IncreasP = 0.048). By increasing severity of cirrhosis from Child A to Child C, normal diastolic function was decreased and diastolic dysfunction was increased. Genovesi et al. showed that echocardiographic findings have no significant differences between groups [Severity of cirrhosis and diastolic dysfunction had a significant correlation . One study showed that 80%, 25%, and 24% of diastolic dysfunction were seen in patients who had severed, moderate, and mild liver fibrosis, respectively . AnotherThe presence of subclinical myocardial disease with cardiac dysfunction and decreased E/A ratio could be emphasized when patients' cardiac status will be improved by paracentesis of ascetic fluid . On the When the duration of cirrhosis was increased, liver cell failure was aggravated and cirrhosis becomes decompensated. In decompensated cirrhosis, there may be a further decrease in the arterial blood pressure owing to the unloading of baroreceptors and renal salt-water excretion is prolonged and incomplete . On otheCardiac dysfunction is a common complication of advanced cirrhosis that can make a variety of disturbances, specially QT interval prolongation and diastolic dysfunction. Diastolic dysfunction is correlated with gender and is more frequent in women. Duration of disease, increased age, and severity of cirrhosis can increase the severity of diastolic dysfunction.Because of high prevalence of diastolic dysfunction in cirrhotic patients and risk of decompensation following invasive procedures, it could be suggested that all patients would be screened routinely by echocardiography before invasive procedures.According to the relation between Child-Pugh score and diastolic dysfunction, we recommend cardiac assessment, especially echocardiographic evaluation in all Child B and Child C (decompensated) cirrhotic patients.


The identification of right ventricular abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) in early stages is still difficult. The aim of this study was to investigate if longitudinal strain based on speckle tracking can detect subtle right (RV) or left ventricular (LV) dysfunction as an early sign of ARVC.Seventeen male patients, fulfilling Task force criteria for ARVC, 49 (32–70) years old, nineteen male first degree relatives 29 (19–73) y.o. and twenty-two healthy male volunteers 36 (24–66) y.o participated in the study. Twelve-lead and signal-averaged electrocardiograms were recorded. All subjects underwent echocardiography. LV and RV diameters, peak systolic velocity from tissue Doppler and longitudinal strain based on speckle tracking were measured from the basal and mid segments in both ventricles. RV longitudinal strain measurement was successful in first degree relatives and controls (95 resp. 86%) but less feasible in patients (59%). Results were not systematically different between first degree relatives and controls. Using discriminant analysis, we then developed an index based on echocardiographic parameters. All normal controls had an index < l while patients with abnormal ventricles had an index between 1–4. Some of the first degree relatives deviated from the normal pattern.Longitudinal strain of LV and RV segments was significantly lower in patients than in relatives and controls. An index was developed incorporating dimensional and functional echocardiographic parameters. In combination with genetic testing this index might help to detect early phenotype expression in mutation carriers. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibro-fatty substitution of the myocardium in the right (RV) and, not infrequently, in the left ventricle (LV). The loss of normal myocardium and the development of scar is associated with electrical instability manifested as ventricular arrhythmia and potential sudden death. A less In addition to resting ECG, imaging of the RV by two-dimensional echocardiography (2D) is the most important screening method. The identification of RV abnormalities using echocardiography is still a major challenge because of the geometric shape of the RV and the patchy involvement of the right ventricular wall with subtle abnormalities at an early stage.Recently, a 2D strain echocardiographic method-7 has beWe hypothesized that right and left ventricular longitudinal strain derived from speckle tracking could be used as a sensitive tool for the detection of subclinical ventricular dysfunction in first degree relatives of ARVC patients.The aim of this study was (1) to test the feasibility of the method when applied on the RV in patients with ARVC and their relatives, (2) to investigate whether first degree relatives of ARVC patients have reduced longitudinal strain by speckle tracking as an early sign of myocardial dysfunction, compared to controls.ARVC affects females less often than males. In thisPatients were referred from hospitals and primary care centres in the southeast of Sweden for investigation and follow-up of ARVC. Since 1994, 19 males have been diagnosed with ARVC based on fulfilment of the Task Force Criteria of the European Society of Cardiology. Two patAll first degree male relatives of ARVC patients , 18 years or older, underwent screening at our tertiary care referral centre. One of them fulfilled criteria for ARVC at the screening visit and was excluded, resulting in 19 relatives, not fulfilling original Task Force criteria, in the study. Kinship has been established from voluntary information from the patients and was not checked with DNA testing.Twenty-four healthy male volunteers were recruited. All were asymptomatic and lacked family history of premature cardiovascular disease. No one was on cardiac medication. The selection of controls was based on matching age to that of the group of relatives, aiming at an age difference < 5 years. Two intended controls were excluded, one due to left bundle branch block (LBBB) on ECG and one due to an abnormal ST-reaction on exercise testing leaving 22 for inclusion. Ethical approval for the study was obtained from the Regional Ethical Review Board in Linköping.The three separate groups - ARVC patients, their first degree relatives and healthy controls - were evaluated by medical history, blood pressure measurement and twelve-lead electrocardiography (ECG). A bicycle exercise test was performed for ruling out significant heart disease. A signal-averaged ECG (SAECG) using 40 Hz high-pass filter was recorded in patients and relatives but not in the healthy volunteers. Positive late potentials were diagnosed when at least two of the three criteria proposed by Breithardt were preEchocardiography was performed with the subjects at rest in the left lateral decubitus position using Vivid 5 or Vivid 7 echocardiographic scanners . All images were stored digitally and analyzed on the Echo Pac work station .A comprehensive 2D, colour, pulsed, and continuous-wave Doppler examination was performed following the recommendations of the American Society of Echocardiography for transthoracic studies. Parasternal long-axis views were used to derive M-mode measurement of left ventricular (LV) end-diastolic dimension, and to determine aortic valve opening (AVO) and closure (AVC). All timing information was in relation to the ECG. The right ventricular (RV) inflow and outflow diameter was measured from the 2D images and indexed to body surface area (RVIT/BSA and RVOT/BSA). Tricuspid annular motion (TAPSE) was recorded at the right ventricular free wall using cross sectional guided M-mode.Colour tissue Doppler myocardial imaging of the LV and RV was performed in the apical four-chamber view, at high frame rate (>100 frames/s). Three consecutive beats were recorded for off line analysis. Mitral and tricuspid annular systolic velocities (Sw) as well as early (Ew) and late diastolic velocities (Aw) were measured in the lateral LV wall, septum and RV free wall with a region of interest (ROI) size of 3 mm.The two dimensional four chamber view was recorded with a frame rate ranging between 40 and 70 frames/s. The endocardial border was traced offline and the ROI was manually adjusted to include the myocardial wall. The software then automatically tracked wall motion over the entire cardiac cycle and measurements were accepted from segments of good tracking quality. The observer was allowed to manually readjust some but not all aspects of the tracking procedure. Systolic longitudinal strain was assessed from the basal and mid segments in the lateral LV wall, septum and RV free wall, FigureAll strain measurements were repeated by the same observer who was blinded to the initial values, at least 5 weeks after the first analysis, in a random sample of 12 echocardiographic studies (4 from each patient group). To define interobserver variability, measurements in the same random sample were assessed by a second independent observer blinded to the results obtained by the previous investigator. The investigator was blinded for the analysis of echocardiographic data.Results were expressed as median (range) for patient details Table and meanmethod) using the formula first proposed by Dahlberg[method was also expressed as % over all means. The coefficient of variation (COV) is the standard deviation of the differences divided by the mean of the measurements and expressed as a percentage.Inter- and intraobserver variability was expressed as standard error of a single determination (SDahlberg. SmethodTwo of the 19 relatives (11%) had a history of occasional palpitations but ventricular ectopy was not seen on the resting ECG or at the exercise test.The resting ECG did not demonstrate inverted T-waves beyond precordial lead V1 in the relatives or in the control group while abnormal, negative T-waves in right sided precordial leads were seen in 13 patients with ARVC (76%). In addition, two had right bundle branch block. One person among the relatives, 3 among controls and 4 patients had incomplete RBBB. Late potentials (defined as fulfilment of at least 2 of 3 criteria) were found in 9/14 (64%) of ARVC patients, but in 2 patients SAECG was not recorded because of frequents arrhythmias and in one case due to ongoing cardiac pacing. Among the first degree relatives 3/19 (16%) had positive late potentials. No one in the control group had positive late potentials.Three (16%) of the first degree relatives were on beta-blockers for mild arterial hypertension. In the ARVC group 13 (70%) had medication for ventricular arrhythmia, arterial hypertension or heart failure. Nine patients (53%) had an implantable cardioverter defibrillator (ICD)..Longitudinal strain measurement using speckle tracking was successful in the left ventricular walls in 15 of 17 (88%) patients, 18 of 19 (95%) first degree relatives and 19 of 22 (86%) controls. For the right ventricular free wall, 2D-strain measurement was feasible in both segments in 10 of 17 (59%) patients. However, two patients had unreliable values in the mid RV). In first degree relatives and controls, 2D-strain in the RV free wall was obtained in 18 of 19 (95%) and 19 of 22 (86%), respectively. Missing data was mostly due to signal dropout, artifact or a very thin wall in the region of interest making wall motion tracking unreliableThe left ventricular diameter was significantly larger in the relatives compared to the controls and the patients. A significantly lower myocardial velocity was detected in the left lateral wall compared to the septum, lowest in the patients and highest in the controls. Except for a lower longitudinal strain value in the basal septum in relatives compared to controls, there were no significant differences between the first degree relatives and controls for the remaining parameters Table.The intraindividual methodological error was for strain 1.6 percentage points (PP) (COV = 8.2%), the same in various locations of the heart. The inter-individual error was, as expected, greater, 2.5 PP (COV = 12.7%), with 2D strain error in the mid level of the RV being significantly greater expressed in absolute but not in relative terms , otherwise no significant differences were found between different parts of the heart.Based on measurement results from the patient group and the volunteers, a multivariate discriminant analysis was performed to detect differences between ARVC-patients and controls in order to investigate the relative role of different parameters from the right and left ventricle for the discrimination of the two groups. The dimensional and functional parameters used for the right ventricle were RVOT/BSA, RVIT/BSA, TAPSE, Sw and longitudinal strain based on speckle tracking of the basal and mid RV free wall segments. For the left ventricle the parameters were LV diameter, LVOT VTI, Sw from the lateral and septal walls, strain based on speckle tracking of the basal and mid segments of the septum and lateral wall. Significant components were reassembled to create separate indices for the right and left ventricles and recalculated for each individual.The following discriminant function was obtained using parameters from the right ventricle:The different age categories (Agecat) were defined as follows: 1 is ≤27, 2 is 28–38, 3 is 39–58 and 4 is >58 years of age and ln is the natural logarithm.The corresponding equation for the left ventricle was:These indices were applied to the group of first degree relatives.Results of the ARVC discrimination index are depicted in FigureNew methods for the assessment of myocardial function have broadened the utility of echocardiography in detecting and understanding the effect of contraction abnormalities of the heart, sometimes in subclinical phases of disease-18.In this investigation we have studied RV and LV function using the speckle tracking method.Speckle tracking was feasible in regions of interest from both ventricles in patients, relatives and controls. However, longitudinal strain measurements in the right ventricular free wall were more often unreliable in patients (41%) than in relatives and controls. This can be explained by the main pathologic feature of the disease, with myocardial degeneration causing thinning of the right ventricular wall, prohibiting tracking with the present version of the software. Using the same software, Teske et al. showed a higher feasibility,20 of spThe inter- and intraobserver variability of speckle tracking measurements was low in both ventricles with low bias and low limits of agreement. As expected the interobserver variability was slightly higher than the intraobserver variability and both measurements were higher for the right ventricular free wall than for the septum and left ventricular lateral wall., but there was no systematic difference in-between relatives and controls.The current study shows that longitudinal speckle derived strain is reduced in the right as well as in the left ventricular walls in patients, confirming the biventricular involvement in ARVC-24, but Echocardiographic findings can be discrete in the early stages of the disease, complicating early diagnosis as Corrado et al. have pointed out.ARVC is a progressive disease that can have variable phenotypic expression. Sometimes, malignant ventricular arrhythmia or sudden cardiac death are the initial manifestations.On the cellular level, it is a disease of the desmosome which affects the cell-adhesion proteins leading to cardiomyocyte detachment and death. ARVC is an autosomal dominant disease in at least 50% of cases,26. The Family screening relies on symptoms and findings in ECG, signal average-ECG, echocardiography and MRI. However echocardiographic abnormalities in the right ventricular wall are still difficult to detect as they can be localised to small areas. Furthermore, visual analysis of RV function from two dimensional grey scale imaging is subjective and can be unreliable for follow-up. New echocardiographic techniques such as measuring the amplitude of tricuspid annular motion (TAPSE) and measurement of myocardial wall velocity using tissue Doppler have improved the accuracy of RV wall motion analysis-30. In rUsing a combination of echocardiographic parameters that were significant in discriminant analysis, we therefore developed an index for the right and the left ventricle based on dimensions and function. Values for these indices in excess of 1 suggest that such an individual expresses features of disturbed ventricular function. While all healthy control subjects had RV and LV indices lower than 1, some of the first- degree relatives deviated from this normal pattern. It is noteworthy that the LV index was frequently abnormal, supporting our previous finding that LV involvement may be an earlier feature of the disease than generally appreciated,22. It s.We suggest that using left and right ventricular indices may be useful, as an abnormal index may be an early sign of the disease. In patients with an established diagnosis of ARVC, the index method may be used as an objective tool for following the progress of the diseaseIn this study we have focused upon male patients as well as their male relatives and matched controls, to avoid that potential gender differences in myocardial function would influence the relationships studied by adding a smaller number of females to the study group at this stage.Inclusion of larger number of patients and relatives would strengthen the results, however expanding numbers is difficult due to the rarity of the disease. It is too early to assess the discriminating power of the proposed index based on this cohort of males, since the group is rather small and needs external validation in independent cohorts. The index is intended to continue to be tested as future first degree relatives are identified and entered into the screening programme.Measurement of longitudinal strain based on speckle tracking was feasible for RV functional analysis in first degree relatives and in the majority of index patients with ARVC. Strain data of individual LV or RV segments were significantly lower in patients than in controls but did not differ between first degree relatives of ARVC patients and control. We have developed an index incorporating a combination of LV and RV dimensional and functional parameters derived from echocardiography that is proposed for the detection of subclinical echocardiographic abnormalities. In combination with genetic testing, this index might help to find early phenotype expression in mutation carriers relatives of ARVC patients, but needs validation in external and preferably larger populations of first degree relatives of ARVC patients.ARVC: Arrhythmogenic right ventricular cardiomyopathy; ECG: Electrocardiogram; SAECG: Signal average electrocardiogram; LBBB: Left bundle branch block; RBBB: Right bundle branch block; AVO: Aortic valve opening; AVC: Aortic valve closure; LVOT VTI: Left ventricular outflow tract velocity time integral; RVOT/BSA: Right ventricular outflow tract related to body surface area; RVIT/BSA: Right ventricular inflow tract related to body surface area; 2D-: Two dimensional; ROI: Region of interest; Sw: Systolic velocity on tissue Doppler imaging; Ew: Early diastolic velocity on tissue Doppler imaging; Aw: Late diastolic velocity on tissue Doppler imaging; TAPSE: Tricuspid annular plane systolic excursion.The authors have no competing interests.MÅA planned the study, investigated all patients, performed measurements and analyses and played a major part in the writing of the manuscript. EN took part in planning the study, reviewed and discussed the manuscript text. JE performed measurements and analyses and took part in writing and reviewing the manuscript. LB took part in the statistical analysis and reviewing the manuscript. All authors have read and approved the final manuscript.


Aging is associated with diastolic dysfunction and increased risk of heart failure, and we investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels.Heart failure is associated with abnormalities of myocardial structure, and plasma levels of the advanced glycation end-product (AGE) NWe performed histological analysis of non-ischemic left ventricular myocardial biopsies and measured plasma levels of the AGEs CML and low molecular weight fluorophores (LMWFs) in 26 men undergoing coronary artery bypass graft surgery who had transthoracic echocardiography before surgery. None had previous cardiac surgery, myocardial infarction, atrial fibrillation, or heart failure.P = 0.02), lower mitral E/A wave ratio , longer mitral valve deceleration time  and lower early diastolic peak velocity of the mitral septal annulus, e’ . However, neither mitral E/A ratio nor mitral septal e’ was correlated with myocardial total, interstitial or perivascular fibrosis (picrosirius red), immunostaining for collagens I and III, CML, and receptor for AGEs (RAGE), cardiomyocyte width, capillary length density, diffusion radius or arteriolar dimensions. Plasma AGE levels were not associated with age. However, plasma CML levels were associated with E/A ratio  and e’  and LMWF levels were associated with E/A ratio . Moreover, the mitral E/A ratio remained correlated with plasma LMWF levels in all patients (P = 0.04) and the mitral septal e’ remained correlated with plasma CML levels in non-diabetic patients (P = 0.007) when age was a covariate.The patients were aged 43–78 years and increasing age was associated with echocardiographic indices of diastolic dysfunction, with higher mitral Doppler flow velocity A wave (r = 0.50, Diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels. Aging is accompanied by increased vascular and ventricular stiffness, diastolic dysfunction and an increased risk of heart failure ε-(carboxymethyl)lysine (CML) and RAGE, and plasma levels of CML, low molecular weight fluorophores (LMWFs) and soluble RAGE. Although we obtained LV biopsies from both men and women, preliminary analysis showed gender-specific differences in myocardial structure We investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels. We performed histological analysis of non-ischemic left ventricular (LV) myocardial biopsies from patients without heart failure or previous myocardial infarction who were undergoing coronary artery bypass graft surgery and had transthoracic echocardiography before surgery. We measured total, interstitial and perivascular myocardial fibrosis, cardiomyocyte size, capillary length density, diffusion radius and arteriolar dimensions. We also measured myocardial expression of the AGE NThe St. Vincent’s Health Human Research Ethics Committee  approved the study protocol. Each participant provided written informed consent to be included in the study.Details of the Cardiac Tissue Bank have been previously described 2 were considered to exceed the abdominal circumference threshold for the metabolic syndrome. A patient had diabetes if a history of diabetes was evident from use of glucose-lowering medications and/or insulin or if fasting plasma glucose was ≥7 mmol/L The metabolic syndrome was defined according to the International Diabetes Federation 2.7Preoperative transthoracic echocardiography was performed and reported by either the referring institution or by St. Vincent’s Health according to the American Society of Echocardiography guidelines Blood hemoglobin and hemoglobin A1c and plasma levels of creatinine were measured as part of the routine pre-surgery workup. All other variables were measured on fasting blood collected on the day of surgery, before induction of anesthesia. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula Details of tissue collection, fixation and histology have been previously described Arterioles were identified by the presence of a layer of media and immunohistochemical staining for elastin showed the blood vessels were relaxed. The tissue was immersion fixed and the arterioles were usually oval in shape because of deformation and/or because they were cut at an oblique angle. We did not attempt to analyze arterioles in longitudinal section and only arterioles in approximate cross- or oblique-section were analyzed for perivascular fibrosis and arteriolar dimensions; these arterioles had diameters (average of maximum and minimum diameter of each arteriole) of 12–106 µm. Perivascular fibrosis was calculated as the ratio of the area of perivascular fibrosis to the total vessel area  Cardiomyocyte width, determined on 4 µm sections of paraffin-embedded tissue (one section per patient) stained for reticulin Capillary length density, which is the length of capillaries per unit volume of tissue, and diffusion radius were determined by analysis of 4 µm sections of paraffin-embedded tissue (one section per patient) immunostained for CD31  using standard stereological techniques Immunohistochemistry for collagens I and III was performed in frozen sections using mouse monoclonal antibodies ab6308 and ab6310 , respectively. Myocardial total collagen I and III densities were calculated using the positive pixel count algorithm  as the area of collagen staining expressed as a percentage of the total myocardial tissue area, after excluding the pericardium. Immunohistochemistry for CML was performed in paraffin sections using a mouse monoclonal antibody as described by Schalkwijk et al. P<0.05.Data are shown as means±SEM or n (%). Correlations were estimated using Pearson correlation coefficients and were considered significant at P = 0.001) and reduced eGFR (P = 0.03). The extent of coronary artery disease  and number of bypass grafts performed were unrelated to age. In addition, diabetes, metabolic syndrome, medication use and hemodynamics, including pulmonary capillary wedge pressure, were not associated with age.The clinical, biochemical and hemodynamic characteristics of the study patients (age range 43–78 years) are shown in Age was not associated with LV ejection fraction, left atrial dimensions, LV mass (not shown) or mitral E wave velocity . HoweverGiven that the strongest correlations between age and echocardiographic indices of diastolic dysfunction were for mitral E/A ratio and mitral septal e′ velocity, we examined the correlation between these echocardiographic parameters and myocardial histology.2, 1.7–10.6 mm2) was unrelated to patient age. Myocardial total, interstitial and perivascular fibrosis were not associated with either mitral E/A ratio or mitral septal e’ velocity  and arteriolar wall area/circumference ratio were not associated with either mitral E/A ratio or mitral septal e’ velocity .Immunostaining for CML was predominantly localized to the media and intima of arterioles and venules, whereas RAGE immunostaining was predominantly localized to the intima of arterioles and venules and to capillaries . Neitherr = 0.21, P = 0.30, n = 26) or non-diabetic patients . Similarly, plasma LMWF levels were not statistically significantly correlated with age in either all patients  or non-diabetic patients . There were, however, significant correlations between plasma levels of CML and LMWFs and echocardiographic indices of diastolic dysfunction (Plasma CML levels were not statistically significantly correlated with age in either all patients (function . In multfunction . There wfunction . Plasma The key finding of this study was that the diastolic dysfunction of aging men undergoing coronary artery bypass graft surgery was not associated with myocardial fibrosis or alteration in cardiomyocyte width, capillary length density, diffusion radius, arteriolar dimensions or myocardial expression of CML and RAGE, but was associated with plasma levels of CML and LMWFs, and these associations were dependent, in part, on age. In addition to diastolic dysfunction, older patients had higher plasma NT-proBNP levels and lower eGFR, consistent with the effects of aging. Our patient population included men with type 2 diabetes and the metabolic syndrome, and in a separate analysis we showed that neither condition affected myocardial structure, microvasculature, or expression of CML and RAGE, apart from reduced perivascular fibrosis of diabetic and metabolic syndrome patients Echocardiographic indices of diastolic dysfunction are associated with an increased risk of heart failure Previous studies reported plasma CML levels were correlated with the severity and prognosis of heart failure Myocardial RAGE expression was predominantly localized to vascular endothelium and capillaries, in agreement with previous studies Our study highlights differences between the effects of aging on the myocardium of humans and animals. In contrast to senescent animals Our study had a number of limitations. The sample size was limited by the need for myocardial biopsies from each patient, with a possibility of type 2 error; our study was therefore largely limited to univariate analyses and many significant correlations may have been missed. In addition, the exclusion of women limited the generalizability of our findings. As expected for patients undergoing coronary artery bypass graft surgery, all had extensive coronary artery disease. However, patients with coronary artery disease were an important group to study because of the high prevalence of coronary artery disease in the community, and there was no association between extent of coronary artery disease and age in our patient population, suggesting that myocardial ischemia was similar across the different ages. Moreover, Redfield et al. In summary, we showed that the diastolic dysfunction of aging was independent of myocardial structure and microvasculature, but was associated with plasma AGE levels. Our data therefore suggest that the increased myocardial fibrosis, cardiomyocyte hypertrophy and reduced microvascular density of heart failure patients


Studies adopting electronic medical records and genomic information are becoming widespread. Through this new modality in research, it is possible to study how genetic variants influence susceptibility towards chronic conditions and can improve patient care.Our aim is to develop a biobank with 2,000 heart failure patients treated in a tertiary cardiology hospital containing electronic medical records data and biologic samples for performing genome-wide association studies for validation and development of medical decision routines aimed at helping the clinical management of patients.Patients between 18 and 80 years old with heart failure diagnosis of different etiologies and left ventricular ejection fraction ≤ 50% in the past 2 years will be eligible for enrollment on the cohort. After consent, patients will be submitted to clinical baseline, echocardiography, cardiograph impedance and biochemical evaluation. Study data will be collected and managed using Research Electronic Data Capture tools. The follow up will take place every 6 months to assess cardiovascular outcomes . Initial analytical strategy will focus on the establishment of the accuracy of electronic medical records extraction protocols for main predictor factors of morbidity and mortality in heart failure.Building a biobank with biologic samples and clinical data of 2,000 heart failure patients we will perform genome-wide association studies. By this way, we pretend to study how genetic variants influence susceptibility towards chronic conditions. Besides, it will be created a working group focused on the development and implementation of algorithms for validation and application of medical routines using the electronic medical records of the Heart Institute (InCor - HCFMUSP).NTC02043431.Current Controlled Trials  Heart failure is an important cause of morbidity and mortality worldwide and in Latin America, the risk factors and epidemiology have peculiarities that are still unclear. Recently, Bocchi et cols discussed the similarities in risk factors compared to developed countries highlighting the prevalence of others causes like Chagas’disease, rheumatic fever and lower total expenditure on health per capita .The mapping of the human genome has enabled new exploration on how genetic variation contributes to health and disease . TechnolThis new approach in research leads on the Personalized Medicine Research Project, a population-based biobank that involves discussions about community consultation and other legal aspects . ActuallRecently, the National Human Genome Research Institute (NHGRI) called on researchers to determine how genetic variants influence susceptibility towards chronic conditions such as diabetes, Alzheimer’s disease, and cardiovascular disease, in order to ultimately improve patient care. For this purpose, the eMERGE  Network – an NHGRI-supported consortium of five institutions – was created to explore the utility of DNA repositories coupled to EMR systems for advancing discovery in genome science .Allied to this new modality in research, the adoption of an online database allows easy access and processing of information collected in a safe and efficient way. The Research electronic data capture (REDCap) is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data capture tools to support clinical and translational research. It was initially developed and deployed at Vanderbilt University, but now has collaborative support from a wide consortium of domestic and international partners .It is clear that new strategies are essential for prevention and treatment of chronic diseases like heart failure. Conditions described in Latin America that has peculiar epidemiology compared to other countries, need further studies. In this scenario, our aim is to develop a biobank containing samples of 2,000 patients with heart failure diagnosis treated in a tertiary cardiology hospital containing electronic medical record and genetic data in genome-wide scale for performing genetic association studies for validation and development of medical decision routines that help the clinical management of these patients.Subjects with systolic heart failure, sequentially included, will be submitted to clinical baseline, echocardiography, cardiograph impedance and biochemical evaluation, which include blood, urine and exhaled breath acetone samples. It will allow the authors to best define the heart failure syndrome, its etiology and its hemodynamic profile. All patients included will also be submitted to clinical follow-up every 6-month for 3 years to assess cardiovascular outcomes: all-cause mortality, cardiovascular mortality, hospitalization for worsening heart failure, current medication use and heart transplantation. The diagnosis of heart failure will be made according to previously published criteria . To defiThe individuals invited to our study will be consecutively selected from the Heart Institute - Clinical Hospital- University of São Paulo Medical School (InCor - HCFMUSP) on their outpatient admission, starting at January 2011.The study protocol was approved by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital from University of São Paulo Medical School (SDC 2368/03/162). Signed informed consent will be obtained from all participants.Patients between 18 and 80 years old with heart failure diagnosis of different etiologies and left ventricular ejection fraction ≤ 50% on two-dimensional transthoracic Doppler echocardiography performed in the past 2 years, who are admitted to the Heart Institute from January 2011, will be eligible for enrollment on the cohort. Specifically, patients with cardiomyopathy due to valvular heart disease enrolled in the study will be those with severe left ventricular dysfunction to the point that they would not be eligible for valve repair or replacement, but rather candidates for heart transplantation.Patients with impaired cognition due to advanced dementia syndrome or severe psychiatric disorder, without telephone access or that refuse to participate will be excluded.During echocardiography, transthoracic images will be obtained with the patient in the left lateral position using Acuson Sequoia 512 (Siemens). The image acquisitions will be standardized in the four windows: parasternal long and short axis, and apical 4 - and 2-chambers. The evaluation of the left ventricular (LV) function will be performed by the echocardiography staff in a blinded way in relation to the protocol and will be conducted according to previously standard recommendations. Left ventricular systolic and diastolic volumes and ejection fraction will be derived from biplane apical views using the modified Simpson’s rule algorithm. Diastolic dysfunction will be determined using Doppler measurements of mitral inflow and Doppler tissue imaging (DTI) of the mitral annulus.All enrolled patients will have fasting serum, exhaled breath acetone, plasma and urine samples collected and stored at -80°C for further analysis.Genomic DNA will be extracted from peripheral leucocytes after a standard salting out protocol . DNA quaThe enrolled patients will have whole-blood RNA collected in fasting state and stored in PAXGene tubes for further analysis according to standard protocol .The exhaled breath acetone has been described as a good biomarker of the diagnosis of heart failure as previously described  and willEnrolled patients will have the opportunity to contribute to genetic associations regarding a number of demographic, clinical and follow-up information. All included individuals will have data on sex, ethnicity, age, duration of symptoms, etiology of heart failure, history of diabetes mellitus, arterial hypertension, smoking, drugs and morbidity outcomes. Anthropometric data like body mass index, heart rate, blood pressure, cardiac rhythm, cardiac dimensions on echocardiography and left ventricle ejection fraction . We will perform serum analyses , exhaled breath acetone dosage and urine analyze. Follow-up will be assessed every 6 months to investigate clinical outcomes as cited above. In addition, the mortality database of São Paulo City Authority will also be periodically scrutinized to discover patient deaths . Follow-up will be carried for all individuals until a 3-year period.Study data will be collected and managed using REDCap electronic data capture tools hosted at the Clinical Hospital from University of São Paulo Medical School. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources .Hemodynamic data will be obtained noninvasively using a monitor CardioScreen 2000  approved for marketing by U.S. Food and Drug Administration (FDA). This device measures the thoracic bioimpedance using the following technique: four dual sensors (each sensor consists of two electrodes) are placed on the patient, on opposite sides of the neck, at a level between the ears and shoulders and on both sides of the chest in the mid-axillary line at the level of the xiphoid process. The electrodes transmit a current of low amplitude and high frequency (2.5 mA and 70 kHz), and detect changes in voltage chest. These alterations in voltage are used to calculate the impedance (Z). The following parameters will be assessed: Cardiac index (CI), Stroke Volume Indexed (SVI), Mean Arterial Pressure (MAP), systemic vascular resistance index (SVRI), Thoracic Fluid Content Indexed (CLTI), velocity index, acceleration index, pre-ejection period, LV ejection time, and systolic time ratio .The genomic DNA samples will be processed and genotyped in the Affymetrix biobank platform for around 800.000 polymorphic markers. For quality control, will be deleted SNPs with genotypes not identified in > 20% of the samples, SNPs with allele frequency rarer (MAF) <1%, or results to Hardy-Weinberg test <0.001. Further, after exclusion of SNPs with quality problems in genotyping, individuals will be analyzed for consistency of genotyping. Individuals with genotyping rate <90% will be excluded.The Heart Institute (InCor - HCFMUSP) had developed and used an in-house system of electronic medical records in the last 2 decades. This information system has medical data that need to be validated for use in systematic clinical research. Using these medical records we pretend to create algorithms for data extraction that enable selection and classification of individuals, or the extraction of continuous variables of medical interest that can be used in research protocols or development of medical decision tools. In summary, we intent to evaluate the validity and specificity of this data collection system and apply it in genetic association studies as well as medical routines of the Institute.Data will be analyzed using SPSS for Windows version 13.0 (SPSS Inc) statistical software.We expect to develop a biobank containing samples and clinical data of 2,000 patients with heart failure diagnosis for performing genetic association studies. Besides, we aim to create a working group focused on the development and implementation of algorithms for validation and application of medical decision routines using our electronic medical record system in order to help the clinical management of patients at the Heart Institute (InCor - HCFMUSP). Furthermore, the project will focus on ethical, legal, political and social impact of this new reality, such as privacy, confidentiality and possible interactions with the community. In this sense, we intend to identify sources of concern among participants regarding current approaches to obtaining informed consent for storage and use of genetic material in clinical research.In this way, with the appropriate use of genetic data in genome-wide scale associated to electronic medical information, we expect to accelerate both the discovery of genetic factors associated with complex diseases such as heart failure and create medical decision routines that help the clinical management of patients in a tertiary cardiology hospital.EMR: Electronic medical records; NHGRI: National Human Genome Research Institute; eMERGE: electronic MEdical records and GEnomics; REDCap: Research electronic data capture; LV: Left ventricular; DTI: Doppler tissue imaging; EBA: Exhaled breath acetone; BNP: B-type natriuretic peptide; FDA: Food and Drug Administration; Z: Impedance; CI: Cardiac index; SVI: Stroke volume indexed; MAP: Mean arterial pressure; SVRI: Systemic vascular resistance index; TFCI: Thoracic fluid content indexed; GWAS: Genome-Wide Association Studies.The authors declare that they have no potential conflicts of interest regarding the present publication.LGP performed the acquisition of data, drafted the manuscript. SBP performed the acquisition of data, helped to draft the manuscript. FGMB performed the acquisition of data, helped to draft the manuscript. JMRS performed the collection of data, carried out part of the molecular genetic studies. RMMS performed the collection of data. NEF carried out part of the molecular genetic studies. FB helped in the patients recruitment. FF helped in the patients recruitment. AJM participated in study design and helped in the patients recruitment. JEK conceived the study, and participated in its design. ACP conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/32/prepub


Previous research shows that the flow dynamics in the left ventricle (LV) reveal important information about cardiac health. This information can be used in early diagnosis of patients with potential heart problems. The current study introduces a patient-specific cardiovascular-modelling system (CMS) which simulates the flow dynamics in the LV to facilitate physicians in early diagnosis of patients before heart failure.The proposed system will identify possible disease conditions and facilitates early diagnosis through hybrid computational fluid dynamics (CFD) simulation and time-resolved magnetic resonance imaging (4-D MRI). The simulation is based on the 3-D heart model, which can simultaneously compute fluid and elastic boundary motions using the immersed boundary method. At this preliminary stage, the 4-D MRI is used to provide an appropriate comparison. This allows flexible investigation of the flow features in the ventricles and their responses.The results simulate various flow rates and kinetic energy in the diastole and systole phases, demonstrating the feasibility of capturing some of the important characteristics of the heart during different phases. However, some discrepancies exist in the pulmonary vein and aorta flow rate between the numerical and experimental data. Further studies are essential to investigate and solve the remaining problems before using the data in clinical diagnostics.The results show that by using a simple reservoir pressure boundary condition (RPBC), we are able to capture some essential variations found in the clinical data. Our approach establishes a first-step framework of a practical patient-specific CMS, which comprises a 3-D CFD model  to simulate the heart and the 4-D PC-MRI system. At this stage, the 4-D PC-MRI system is used for verification purpose rather than input. This brings us closer to our goal of developing a practical patient-specific CMS, which will be pursued next. We anticipate that in the future, this hybrid system can potentially identify possible disease conditions in LV through comprehensive analysis and facilitates physicians in early diagnosis of probable cardiac problems. Research commonly uses computational fluid dynamics (CFD) simulation to investigate cardiovascular problems. Most of the research in this field focuses on a specific region of the heart ,2 ratherEmphasis on the left ventricle (LV) of the heart dates back to the 1970s . Early eVortex formation in the LV has also attracted recent attention. Fortini et al.  investigSeveral numerical studies of flow within LV also show the complexity of vortex formation. Domenichini et al.  used a mSaber et al.  used patThis study develops (and introduces) a 3-D CFD based, patient-specific cardiovascular modelling system in order to facilitate the physician's early diagnosis of possible cardiac problems in practical application. The tools comprise of a 3-D CFD model to simulate the heart and a 4-D (3-D in space and 1-D in time) PC-MRI system. This hybrid system can potentially identify possible disease conditions in the LV through analyzed vorticity, kinetic energy, hemodynamics, pressure, and shear stress. Approximately 30% of all heart attacks are fatal . The avaAs a first step, we concentrate on verifying the results of CMS with clinical data in this paper. These results and comparisons are essential for the subsequent model improvements and practical implications. The next section describes the methodology of the cardiovascular modelling system, followed by a detailed description of the 4-D PC-MRI system and its capabilities. The numerical method developed by Mcqueen and Peskin  will be Developing an accurate CFD based patient-specific cardiovascular modelling-system involves integrating analyzed data from the 4-D PC-MRI system (hardware) into the IBM heart model (software). Figure In the CMS, the boundary conditions are specified at five major inflow and outflow sources, including 1) superior vena cava (SVC); 2) inferior vena cava (IVC); 3) pulmonary vein (PV); 4) pulmonary artery (PA); and 5) aorta, as shown in Figure The CFD heart model aids in close investigation of the entire process within the LV to examine the possibility of observing disease-related dysfunctions in the dynamics of transmitral blood flow during early LV diastole. Combining the non-invasive 4-D PC-MRI information with the quasi-realistic heart model provides a unique opportunity to evaluate cardiovascular hemodynamic before complete heart failure. Here, we emphasize more on the initial comparison between the modelled flow dynamics in LV with the clinical data for a healthy subject to obtain a better understanding of the current technique.2 with matrix = 256 × 192 and the section thickness is 6 mm. This forms the volume images at 256 × 192 × 8 , which approximates to an actual size of 307 × 230 × 48 mm3. Each "z=" plot below represents the orthogonal coordinate section of the xy plane. Only 8 slices in the z direction are used due to the constraint of the PC-MRI system. Hence, the images can only provide qualitative flow dynamics in patients and volunteers. We anticipate the CMS shall provide us better details with a reasonable comparison with the PC-MRI system.The latest 4-D time-resolved PC-MRI, located at the National Taiwan University Hospital, provides enhanced and more realistic physiological information for the CFD flow simulation. This system acquired images using a 3T MR imaging system  with standard body coil , which aThe test subject of the 4-D PC-MRI system for this initial test is a healthy 35 year-old female volunteer with no underlying disease. The study was approved by the Institution Review Board (IRB) at the hospital. MRI images over an entire heart cycle were taken. A snapshot image taken at T = 0.2 in Figure The IBM algorithm is based on Lai and Peskin , and verx = , u = , v, w), is the fluid velocity and x, t) p(is the fluid pressure. μ and ρ represent the fluid viscosity and density respectively. The force density (with respect to x d= dxdydz) acting on the fluid is f = , fy, fz). The s tracks a material point of the immersed boundary and the boundary force density (with respect to ds) is F = , Fy, Fz). Equations (3) and (4) estimate the interaction between the immersed boundary and the fluid. Equation (5) represents the boundary force resulting from the boundary configuration at time t, where the function S satisfies a generalized Hooke's law if the boundary is elastic.In this case, x, y, z which covers the entire fluid domain. The moving grid represents the boundary or fibers of the heart. At each time step, the force acting at each point on the fiber is calculated using Equation (5). These fibers exert force onto the fluid, represented by the Cartesian fixed grid, and the force on the fluid is calculated using Equation (3). The resulting velocity at time step (n+1/2) is then obtained by solving Equations (1) and (2) using the fractional step method, which solves the momentum and the pressure Poisson equations. With this, one can return to interpolate the velocity of the fiber from its surrounding velocity of the fluid. The fibers then move to their new positions at t = n+1/2 based on their velocities. With the known velocities and positions of the fibers at t = n+1/2, the solution process is repeated, but now they are used to take a full time step from t = n to n+1. This results in a time-centered or Crank-Nicolson scheme which has "formal" second-order accuracy [Two sets of grids, fixed and moving, are adopted in the CMS. The fixed grid represents the Cartesian grid accuracy . The whoEquation . The resConstructing the 3-D CMS includes a few steps. The most fundamental component is the boundary points, which are joined together to form fibers. The fibers with the same number of points are clustered together as a group, while a bunch is made up of groups. The combined bunches form the heart. Hence, the entire heart model is made up of about 4,000 fibers consisting of about 600,000 boundary points. The fiber connections are based on studies of the hearts of dog and hogs which were bathed in a substance that dissolves the connective tissue between the muscle fibers. More details about the construction of the heart can be found in Mcqueen and Peskin . Fiber e3 and 2563 grids at the early stage. Figure The fixed Cartesian grid uses uniform 128 × 128 × 128 grid points with a domain size of approximately 17 × 17 × 17 cm cube. The width of 17 cm is based on a domain of 64 meshwidths. A mitral ring radius of 5.85 meshwidths represents the 10 cm circumference of the human mitral ring. A grid refinement study was carried out by running the simulation partially up to T = 0.2 with a grid size of 256 × 256 × 256 grid points. Qualitative visualization shows the similarity between both heart expansion and contraction of the 128Assuming a peak physiological Reynolds number (Re) of 6000, the current number of grid points is clearly insufficient to resolve the boundary layer in the simulation. At Re ≈ 6000, turbulent flow is expected. As a preliminary study, the current simulation assumes a laminar flow and does not use any turbulence model. Note that the main purpose of this study is not to create an exact model of the heart, which will require very high computational resources to resolve the detailed forces and FSI. This is also due to the fact that the immersed boundary method of Peskin  is not aA new single heartbeat, together with the initial transient, requires 57,344 time steps. An initial transient period is required because the simulation may not run successfully if the LV is empty. The LV must be filled with sufficient blood before conducting the actual cardiac cycle. This filling period runs from t = 0 to 0.34 s. Therefore, our analysis of the cardiac cycle starts from t = 0.34 s to t = 1.14 s (the complete cardiac cycle T lasts 0.8 s). The time t = 0.34 s corresponds to the onset of the diastolic phase. Hereafter, the time is normalized by the complete cardiac cycle (T = 1.0) for simplicity.-5 s, the current simulation obtains results from the first heartbeat after the initial transient.Simulation of a single heartbeat takes approximately 42 hours on a Linux cluster comprising the Intel Xeon Woodcrest Quad-Core 5345 2.33GHz processors with openmp parallelization enabled. Subsequent heartbeats require 32,768 time steps. With an assumed heartbeat lasting 0.8 s and time step 2.44 × 103 and 0.03125 cm2/s[As mentioned earlier, the boundary condition for the CMS is specified at five locations of the heart. Cyclic pressure boundary conditions are specified. Similar to Mcqueen and Peskin , this wo125 cm2/s. Althoug125 cm2/s, we analFigure Q represents the flow rate through the mitral during the diastole , and through the aortic valve during the systole . The graph of Fortini et al. in Figure Figure The vortex dynamics is the most important characteristics in LV. Figure z = 0 and 1, the cross-section of the vorticity contour comes from the location z = 0.56 . For the comparison, four different sections out of eight from the 4-D PC-MRI are also chosen to calculate the total KE. Figure -7 joules are not shown. We also use colors to indicate the KE level.The variation of kinetic energy (KE) of blood flow in the LV indicates the work of the pumping heart. Figure 3/s) during the S-wave seems plausible. The magnitude should be similar to that of the earlier outflow (around T = 0.45) because the mitral valve is closed at this time, as shown in the bottom left of Figure We discussed the flow rates through the PV and aorta in the simulation Figure . The larThe comparison in Figure This section discusses the evolution of vorticity in the LV throughout the entire cardiac cycle and emphasizes vortex dynamics in the LV of the heart during diastole. As mentioned by Domenichini et al. , many reThe formation of the vortices and their respective locations can be explained using Figure Figure The normalized total KE of the heart using the 4-D PC-MRI system is also compared in Figure The current study implemented the CMS based on the code by Mcqueen and Peskin . We compModeled vorticity fields show similar results compared to the experiments conducted by Fortini et al. . Both siThe results show that using a simple RPBC is able to capture some of the essential variations found in the clinical data in some basic analysis, which encourages further aid of physician's diagnostics using the CMS approach. These include the peaks captured in Figure The presented approach establishes a first-step framework of a practical patient-specific CMS, which comprises a 3-D CFD model to simulate the heart and the 4-D PC-MRI system. At this stage, the 4-D PC-MRI system is used for verification purpose rather than input. This study brings us closer to our goal of developing a practical patient-specific CMS, which will be pursued next. In practice, conducting a patient-specific CMS in advance can accurately predict and visualize the blood flow in the heart, thus providing a general understanding and adequate evaluation of the heart flow dynamics noninvasively. Since the 3-D modelling component of this patient-specific CMS is still computationally expensive, this system can be used ideally for the purpose of pre-operation evaluation or surgical planning. It can solve the common echocardiographic windows problem for many patients. Most important of all, the vortex dynamic and other complicated flow dynamics can be comprehensively revealed and provided to the physicians for necessary treatment. This can greatly simplify the diagnostic process compared to using MRI, echocardiography or other techniques, which have difficulties as mentioned earlier.Written informed consent was obtained from the patient for publication of this study and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal written informed consent was obtained from the patient for publication of this report.The authors declare that they have no competing interests.WBT and YHT conceived the study, participated in the design of the study and drafted the manuscript. LYL and WYT provided the 4-D MRI data and helped to explain the blood circulation in the heart. WBT and YHT carried out the numerical simulations and participated in the design and coordination of the work and helped to revise critically the manuscript. All authors read and approved the final manuscript.